Concomitant administration of glucocorticoid receptor modulators and cyp3a inhibitors

ABSTRACT

Applicant provides methods of treating diseases including Cushing&#39;s syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor modulator (GRM) and steroidogenesis inhibitors, and by concomitant administration of a GRM and CYP3A inhibitors. The GRM may be, e.g., mifepristone; the CYP3A inhibitors or steroidogenesis inhibitors (collectively “inhibitors”) may be, e.g., ketoconazole or itraconazole. Inhibitors may cause toxicity or other serious adverse reactions; concomitant administration of inhibitors with other drugs may increase the risk of such toxicity and adverse reactions due to the inhibitors and/or the other drugs. Applicant has surprisingly found that GRMs may be administered to subjects receiving inhibitors without increasing the risk of adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole or itraconazole, providing safe concomitant administration of the GRM and ketoconazole or itraconazole. In embodiments, the GRM dose may be reduced during concomitant administration of the GRM with inhibitors

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, claims priority to, and thebenefit of, U.S. application Ser. No. 17/544,859, filed Dec. 7, 2021,which is a continuation of U.S. application Ser. No. 16/482,656, filedJul. 31, 2019, now abandoned, which is a 371 National Stage Applicationof PCT/US2018/020336, filed Feb. 28, 2018, which claims the benefit ofU.S. Provisional Application No. 62/466,867, filed Mar. 3, 2017 and62/465,772, filed Mar. 1, 2017. Each and every one of the above patentapplications is hereby incorporated by reference in its entirety for allpurposes.

BACKGROUND

Steroid molecules, such as steroid hormones, play an important role inbodily functions and in bodily responses to infectious and otherdiseases, and to the environment. Many steroid molecules are synthesizedin the body, or are produced from molecules consumed in the diet.Steroid molecules which act as hormones in the body include estrogen,progesterone, testosterone, and cortisol. Some steroid molecules havemedicinal effects. Inhibition of steroid synthesis or metabolism can beuseful in the treatment of some disorders.

Cortisol, a steroid molecule, plays an important role in many bodilyfunctions. Cortisol exerts effects by binding to cortisol receptors,which are present in most tissues in the body. However, dysregulation ofcortisol may have adverse effects on a subject. For example, Cushing'ssyndrome, caused by excess levels of cortisol, is characterized bysymptoms including elevated blood pressure, elevated blood glucose,increased weight, increased mid-section perimeter, other pre-diabeticsymptom, a “moon-face” facial appearance, immune suppression, thin skin,acne, depression, hirsutism, and other symptoms. Clinical manifestationsof Cushing's syndrome include abnormalities in glucose control,requirement for anti-diabetic medication, abnormalities in insulinlevel, abnormal psychiatric symptoms, cushingoid appearance, acne,hirsutism, and increased or excessive body weight, and other symptoms.

One effective treatment of cortisol dysregulation is to block thebinding of cortisol to cortisol receptors, or to block the effect ofcortisol binding to cortisol receptors. Mifepristone binds to cortisolreceptors, and acts to block such binding and to block the effect ofcortisol on tissues. Mifepristone is11-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one).

Another effective treatment of cortisol dysregulation is to reduce thesynthesis of cortisol, e.g., by reducing or blocking steroid synthesis.A “steroidogenesis inhibitor” is a compound which reduces or blocks thesynthesis of steroid molecules (including, e.g., cortisol) whenadministered to a subject. Steroidogenesis inhibitors include, forexample, ketoconazole, metyrapone, etomidate, and other drugs.

Many enzymes are involved in steroid synthesis and in steroidmetabolism, including cytochrome P450 enzymes, encoded by CYP genes.Inhibiting steroid synthesis may lower the levels of steroids,including, e.g., cortisol, in the blood. For example, CYP3A enzymes playimportant roles in the synthesis of steroid hormones such as cortisol.In addition, such enzymes may also metabolize drugs that may beadministered to subjects. For example, cytochrome P450 3A4 (CYP3A4) hasbeen shown to be involved in mifepristone metabolism in human livermicrosomes.

However, many drugs inhibit the levels or actions of CYP3A gene products(termed “inhibit CYP3A”). The following drugs inhibit CYP3A:ketoconazole, itraconazole, fluconazole, cimetidine, nefazodone,ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir,boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole,saquinavir, telaprevir, telithromycin, and voriconazole, among manydrugs which inhibit CYP3A. For example, the following drugs stronglyinhibit CYP3A (i.e., increase AUC (area under the concentration-timecurve) by 10-fold or greater of sensitive index substrates), eitheralone or in combination with other drugs: boceprevir, cobicistat,conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir,indinavir, ritonavir, itraconazole, ketoconazole, lopinavir,pantaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir,telaprevir, tipranavir, troleandomycin, and voriconazole.

Ketoconazole is an exemplary and an important steroidogenesis inhibitorand is a strong CYP3A inhibitor. Ketoconazole (chemical name:1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)is administered for the treatment of fungal infections; it also affectssteroid metabolism by inhibiting steroidogenesis, and hasanti-glucocorticoid and anti-androgen effects due to its interferencewith enzymatic conversion of cholesterol to hormones such as cortisoland testosterone. Ketoconazole has effects on liver enzymes and thegastrointestinal (GI) tract, among other effects (Fleseriu andCastinetti, Pituitary 19:643-653 (2016)).

Ketoconazole inhibits steroid synthesis and is thus useful in thetreatment Cushing's syndrome; in the treatment of prostate cancer andother androgen-sensitive cancers; to reduce estrogen or progesteroneproduction (e.g., in patients with hormone-sensitive cancers such asbreast cancer and ovarian cancer); and in other treatments.

A drug such as ketoconazole is typically metabolized and excreted by asubject over time following administration. An effective dose isdetermined based on the expected amounts of metabolism and excretion ofthe drug. Changes in the amounts or rates of metabolism and/or excretionof a drug will affect the dose required, and may make an otherwise safedose, if metabolism or excretion changes, into either a less, orineffective dose, or a more effective or even toxic dose.

However, although sometimes clinically useful, ketoconazole may haveadverse, including seriously toxic, effects (Fleseriu and Castinetti,Pituitary 19:643-653 (2016)). The U.S. Food and Drug Administrationissued a Drug Safety Communication (Jul. 26, 2013 Safety Announcementregarding NIZORAL® (ketoconazole)) warning of potentially fatal liverdamage associated with oral ketoconazole treatment and warning of therisk of adrenal insufficiency, also a potentially fatal disorder. TheSafety Announcement warned: “Nizoral tablets can cause liver injury,which may potentially result in liver transplantation or death.” TheSafety Announcement further stated: “Nizoral tablets may interact withother drugs a patient is taking and can result in serious andpotentially life-threatening outcomes, such as heart rhythm problems.”Thus, ketoconazole can be quite toxic if administered in excessiveamounts, or if it is administered to sensitive individuals, particularlywhen administered systemically (as opposed, e.g., to topically). Thistoxicity can lead to liver damage (sometimes requiring livertransplantation). Other CYP3A inhibitors, including, e.g., itraconazole,ritonavir, and other CYP3A inhibitors as discussed herein, may havesimilar effects and may require similar warnings.

The simultaneous, or nearly simultaneous (e.g., concomitant) presence oftwo drugs in a subject may alter the effects of one or the other, orboth, drugs. Such alterations are termed drug-drug interactions. Forexample, the required dose of a drug is often strongly affected bytaking the amount and rate of its degradation in, and elimination from,the body (e.g., by liver or kidney action). However, the presence of asecond drug in the body, which is also being acted upon by the liver andkidney, can have significant effects on the amount and rate ofdegradation of the first drug, and can increase the amount of the firstdrug that remains in the body at a given time beyond the amount thatwould have been present at that time in the absence of the second drug.Thus, the presence of a second drug can often increase the effectivedose of the first drug. Where the first drug has toxic side effects,such an increase in effective dose of the first drug may lead todangerous toxicity that would not have been expected were the seconddrug not present.

Concomitant administration of different drugs often leads to adverseeffects since the metabolism and/or excretion of each drug may reduce orinterfere with the metabolism and/or excretion of the other drug(s),thus increasing the effective concentrations of those drugs as comparedto the effective concentrations of those drugs when administered alone.Thus, concomitant administration of drugs is often expected to increasethe risk of toxic effects of one or both of the co-administered drugs.Some drugs, such as ketoconazole, present risk of liver damage(including severe cases including liver failure and even requiring livertransplants) and other toxic effects when administered alone; the riskof such toxic effects is believed to be increased when other drugs areconcomitantly administered. Where a drug, such as ketoconazole, is knownto present a high risk of toxic effects, clinicians will typically avoidits concomitant administration with other drugs.

The plasma levels of a drug are affected not only by the amountadministered, but may also be affected by the amount (and rate) of itsmetabolism. For this reason, regulatory agencies typically require“drug-drug interaction” (DDI) studies to determine the effects ofconcomitant administration of drugs. Many enzymes, including cytochromeP450 enzymes (e.g., the cytochrome P450-3A enzymes, termed “CYP3A”enzymes), provide significant amounts of the metabolism of administereddrugs. Drugs that inhibit metabolic enzymes such as CYP3A can causeincreases in the plasma levels of other drugs which are administered orare present at times where there are sufficient levels of both drugs ina subject. Such increases can be significant. For example, Greenblatt etal. (Brit. J. Clin. Pharmacol. 80(3):342-350 (2015) reviewed 38published studies involving 411 subjects, and report that concomitantlyadministered representative CYP3A inhibitors increased plasma levels oforally administered midazolam (as measured by the area under theconcentration-time curve “AUC”) by more than 11-fold (ketoconazole);more than 7-fold (itraconazole); more than 6-fold (clarithromycin); andmore than 14-fold (ritonavir). Thus, CYP3A inhibitors typically have avery large effect on plasma levels of other, concomitantly administered,drugs.

The U.S. The Food and Drug Administration (FDA) notes that “Patientsfrequently use more than one medication at a time. Unanticipated,unrecognized, or mismanaged DDIs [drug-drug interactions] are animportant cause of morbidity and mortality associated with prescriptiondrug use” (page 2 of “Clinical Drug Interaction Studies—Study Design,Data Analysis, and Clinical Implications Guidance for Industry”). Thissame U.S. FDA report names multiple “strong CYP3A” inhibitors(increasing AUC of sensitive CYP3A substrates by more than 5-fold),including many (e.g., ketoconazole, itraconazole, ritonavir, boceprevir,cobicistat, conivaptan, telaprevir, troleandomycin, and variconazole,among others) which increase AUC of sensitive CYP3A substrates by morethan 10-fold. Thus, large plasma level increases of greater than 5-foldor greater than 10-fold would be expected for CYP3A substrates, such asmifepristone, when concomitantly administered with a strong CYP3Ainhibitor such as, e.g., ketoconazole, itraconazole, ritonavir, orothers.

The use of ketoconazole, itraconazole, or of some other drug along with,e.g. mifepristone, may be thought to be required for successfultreatment of a patient. However, since concomitant administration of aCYP3A substrate (such as, e.g., mifepristone or other glucocorticoidreceptor modulator) with a CYP3A inhibitor (such as ketoconazole,itraconazole, or others) would be expected to raise the levels of theCYP3A substrate to unsafe levels, or could expose the patient todangerous or toxic effects of one or the other drug, a physician mayforego the concomitant use of ketoconazole, itraconazole, or other drugwhich may have otherwise been thought to be required for successfultreatment.

However, patients may require treatment with multiple drugs, despite thepossible disadvantages that can have deleterious consequences for thepatient.

Accordingly, improved methods of treatment allowing the administrationof other drugs along with CYP3A inhibitors (such as, e.g., ketoconazole,itraconazole, and others) and along with steroidogenesis inhibitors(such as, e.g., ketoconazole, itraconazole, and others) are desired.

SUMMARY

Applicant discloses herein that CYP3A inhibitors such as, e.g.,ketoconazole, itraconazole, and others, may be concomitantlyadministered with glucocorticoid receptor modulators (GRMs) such as theGR antagonist (GRA) mifepristone. Such concomitant administration of aCYP3A inhibitor such as ketoconazole and a GRM such as mifepristone isbelieved to be safe for the subject, and to provide the therapeuticbenefits of both drugs to the subject, and may allow the reduction inthe amount of a GRM, or of a CYP3A inhibitor, administered to thesubject; such reduction may reduce the risk of toxic effects of theCYP3A inhibitor concomitantly administered with the GRM. In embodiments,the CYP3A inhibitor is a strong CYP3A inhibitor. Such concomitantadministration of a CYP3A inhibitor such as ketoconazole and a GRM suchas mifepristone is believed to be safe for the subject, and to providethe therapeutic benefits of both drugs to the subject, may allow thereduction in the amount of GRM administered to the subject, and mayallow the reduction in the amount of a CYP3A inhibitor administered tothe subject; such reductions may improve treatment of the patient andmay reduce the risk of toxic effects of the CYP3A inhibitor.

Applicant discloses herein that steroidogenesis inhibitors may beconcomitantly administered with glucocorticoid receptor modulators(GRMs) such as the GR antagonist (GRA) mifepristone. Such concomitantadministration of a steroidogenesis inhibitor and a GRM such asmifepristone is believed to be safe for the subject, and to provide thetherapeutic benefits of both drugs to the subject, and may allowconcomitant administration of a GRA and a steroidogenesis inhibitor, mayallow the reduction of the amount of GRM administered to the subject, ormay allow the reduction in the amount of a steroidogenesis inhibitoradministered to the subject; such reductions may reduce the risk oftoxic effects of the steroidogenesis inhibitor. Such concomitantadministration of a steroidogenesis inhibitor and a GRM such asmifepristone is believed to be safe for the subject, and to provide thetherapeutic benefits of both drugs to the subject, and may allow thereduction in the amount of GRM or of a steroidogenesis inhibitoradministered to the subject; such reduction may improve treatment of thesubject and may reduce the risk of toxic effects of the steroidogenesisinhibitor.

For example, Applicant has surprisingly discovered that mifepristone maybe administered to patients concomitantly receiving ketoconazole. Forexample ketoconazole may be administered to patients previously, orconcomitantly, also receiving mifepristone so that the patientconcomitantly receives ketoconazole and mifepristone. Such concomitantadministration of ketoconazole and mifepristone is typically safe forthe patient, provides the therapeutic benefits of both drugs to thepatient, and may allow the reduction in the amount of mifepristoneadministered to the subject; such reduction may provide an effectivedose of mifepristone that is a lower dose, yet still provides similarplasma mifepristone levels as, and may be as effective as, the dose ofmifepristone administered in the absence of ketoconazole. Suchconcomitant administration of ketoconazole and mifepristone provides thetherapeutic benefits of both drugs to the patient, may allow a reductionin the amount of mifepristone administered to the patient, and may allowthe reduction in the amount of ketoconazole administered to the patient;such reduction may reduce the risk of toxic effects of ketoconazole, andmay improve the treatment of the patient.

Applicant's surprising discovery is believed to apply to patientssuffering from a disease or disorder and receiving a CYP3A inhibitor,including a strong CYP3A inhibitor such as ketoconazole; such patientssuffering from a disease or disorder may be safely administered a GRM,such as mifepristone, concomitantly with the administration of a CYP3Ainhibitor such as ketoconazole. Such concomitant administration isbelieved to be safe for the patient. For example, concomitantadministration of ketoconazole and mifepristone surprisingly does notincrease the risk of ketoconazole toxicity in the patient, and isbelieved to be safe for the patient. In particular, Applicant disclosesherein that Cushing's syndrome patients receiving ketoconazole may besafely administered mifepristone concomitantly with the administrationof ketoconazole. Such concomitant administration of ketoconazole andmifepristone to a patient suffering from Cushing's syndrome is believedto be safe for the patient suffering from Cushing's syndrome, which ischaracterized by hypercortisolism. Patients suffering from Cushing'ssyndrome, such as those suffering from endogenous Cushing's syndrome,may suffer hyperglycemia secondary to hypercortisolism. Concomitantadministration of a GRA (such as, e.g., mifepristone) and a CYP3Ainhibitor (such as, e.g., ketoconazole) as disclosed herein is believedto be safe, and to be suitable for controlling hyperglycemia secondaryto hypercortisolism in a patient with endogenous Cushing's syndrome.

In embodiments, a method of treating a patient with Cushing's syndrome,the patient currently taking a GRA at an original dosage, comprisesreducing the amount of GRA from said original dosage to an adjusteddosage that is less than the original dosage when the patient isreceiving concomitant administration of a CYP3A inhibitor. Inembodiments, a method of controlling hyperglycemia secondary tohypercortisolism in a patient with endogenous Cushing's syndrome, thepatient currently taking a GRA at an original dosage, comprises reducingthe amount of GRA from said original dosage to an adjusted dosage thatis less than the original dosage when the patient is receivingconcomitant administration of a CYP3A inhibitor. In embodiments of suchmethods, the adjusted dosage is less than the original dosage by atleast an amount selected from about 5%, 10%, 15%, 20%, 25%, 30%,33^(1/3)%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 66^(2/3)%, 70%, 75%, 80%,85%, and 90% of the original dosage. In embodiments, the adjusted dosageis less than the original dosage by at least 10% of the original dosage.In embodiments, the adjusted dosage is less than the original dosage byat least 25% of the original dosage. In embodiments, the adjusted dosageis less than the original dosage by at least 33^(1/3)% of the originaldosage. In embodiments, the adjusted dosage is less than the originaldosage by at least 50% of the original dosage.

In embodiments, where a GRM such as mifepristone would be prescribed ata first GRM dose, the amount of the GRM (such as mifepristone)administered, when co-administered with a steroidogenesis inhibitor orCYP3A inhibitor such as ketoconazole, may be reduced to a reduced GRMdose that has a smaller amount of GRM as compared to the first GRM doseyet provide effective treatment at the reduced GRM dose co-administeredwith a steroidogenesis inhibitor such as ketoconazole. In embodiments,the clinical status of a subject receiving a reduced GRM doseconcomitantly with a steroidogenesis inhibitor may be monitored forclinical response, e.g., for clinical response to the GRM (such asmifepristone). Monitoring for clinical response may include monitoringfor clinical effect of the GRM, including clinical efficacy of the GRM;for clinical effect of a steroidogenesis inhibitor of CYP3A inhibitor;for possible adverse reaction to a steroidogenesis inhibitor or CYP3Ainhibitor, or the use of a steroidogenesis inhibitor or CYP3A inhibitorin combination with the GRM; for possible side-effects of asteroidogenesis inhibitor or CYP3A inhibitor; for possible side-effectsof the use of a steroidogenesis inhibitor or CYP3A inhibitor incombination with the GRM; or combinations thereof.

In embodiments, the reduced GRM dose may be increased as necessary andas safe for the patient according to such monitoring of the patient. Inembodiments, the reduced GRM dose may be titrated upwards as necessaryand as safe for the subject according to such monitoring of the patientin order to achieve effective treatment of Cushing's syndrome whileremaining safe for the patient with regard to possible adverse effectsof the concomitant administration of the GRM and the CYP3A inhibitor, orof the concomitant administration of the GRM and the steroidogenesisinhibitor.

In embodiments, where a GRM such as mifepristone would be prescribed ata first GRM dose, the amount of the GRM (such as mifepristone)administered, when co-administered with a CYP3A inhibitor, including astrong CYP3A inhibitor such as ketoconazole, may be reduced to a reducedGRM dose that has a smaller amount of GRM as compared to the first GRMdose yet provide effective treatment at the reduced GRM doseco-administered with a CYP3A inhibitor such as ketoconazole. Inembodiments, the clinical status of a patient receiving a reduced GRMdose concomitantly with a CYP3A inhibitor may be monitored, e.g., forclinical effect of the GRM, for clinical effect of the CYP3A inhibitor,for possible adverse reaction to the CYP3A inhibitor or its use incombination with the GRM, for possible side-effects of the CYP3Ainhibitor or its use in combination with the GRM, or combinationsthereof. In embodiments, the reduced GRM dose may be increased asnecessary and as safe for the patient according to such monitoring ofthe patient. In embodiments, the reduced GRM dose may be titratedupwards as necessary and as safe for the patient according to suchmonitoring of the patient in order to achieve effective treatment ofCushing's syndrome while remaining safe for the patient with regard topossible adverse effects of the concomitant administration of the GRMand the CYP3A inhibitor.

Accordingly, Applicant discloses herein that a steroidogenesis inhibitormay be administered to patients concomitantly receiving administrationof a GRM. Accordingly, Applicant discloses herein that a CYP3A inhibitormay be administered to patients concomitantly receiving administrationof a GRM. For example, Applicant discloses herein that ketoconazole, asteroidogenesis inhibitor and a CYP3A inhibitor, may be administered topatients suffering from a disease or disorder, such as, e.g., Cushing'ssyndrome, who are concomitantly receiving administration of a GRM suchas mifepristone. Such concomitant administration of both a GRA (such asmifepristone) and a CYP3A inhibitor (such as ketoconazole) may beadministered to a patient suffering from endogenous Cushing's syndrometo control hyperglycemia secondary to hypercortisolism in the patient.

Accordingly, Applicant discloses herein that GRMs may be administered tosubjects previously, or concomitantly, also receiving administration ofa steroidogenesis inhibitor or a CYP3A inhibitor. For example, Applicantdiscloses herein that GRMs may be administered to subjects sufferingfrom a disease or disorder, such as, e.g., Cushing's syndrome, whopreviously, or are concomitantly, also receiving administration of asteroidogenesis inhibitor such as ketoconazole or a CYP3A inhibitor suchas ketoconazole or itraconazole. Applicant discloses methods forconcomitant administration of a GRM and a steroidogenesis or CYP3Ainhibitor such as ketoconazole useful for treating a subject in need ofsuch administration. Subjects in need of such administration includesubjects suffering from a disease or disorder, and include subjectssuffering from Cushing's syndrome. Applicant further discloses that suchadministration of a GRM and a steroidogenesis inhibitor such asketoconazole or a CYP3A inhibitor such as ketoconazole or itraconazoleis typically safe for the subject, and provides the therapeutic benefitsof both drugs to the subject. In embodiments, such concomitantadministration of an inhibitor such as ketoconazole or itraconazole anda GRM may allow the reduction in the amount of GRM, or of asteroidogenesis or a CYP3A inhibitor such as ketoconazole, that isadministered to the subject; such reductions may reduce the risk oftoxic effects of a steroidogenesis inhibitor such as ketoconazole, or aCYP3A inhibitor such as ketoconazole or itraconazole, such as, e.g.,reduce the risk of liver damage to the subject. The GRM may be, e.g.,mifepristone.

Applicant has surprisingly discovered that a steroidogenesis or a CYP3Ainhibitor such as ketoconazole may be concomitantly administered withGRMs, such as GRAs, so that concomitant administration of asteroidogenesis or a CYP3A inhibitor such as ketoconazole and a GRA forexample may provide safe and effective treatment of a patient in need oftreatment. A patient receiving concomitant administration of asteroidogenesis inhibitor such as ketoconazole or a CYP3A inhibitor suchas ketoconazole or itraconazole and a GRA may be, for example, a patientin need of treatment for Cushing's syndrome (including Cushing'sDisease), breast cancer, prostate cancer, ovarian cancer, or otherhormone-sensitive cancer. In embodiments, such a patient in need oftreatment may receive concomitant administration of a steroidogenesisinhibitor such as ketoconazole or a CYP3A inhibitor such as ketoconazoleor itraconazole and a GRA, such as mifepristone. In embodiments, such apatient in need of treatment may receive concomitant administration ofketoconazole and mifepristone.

The methods, compositions, and kits disclosed herein are suitable foruse in treating patients suffering from Cushing's syndrome (includingCushing's Disease); or from prostate cancer and other androgen-sensitivecancers; or from breast cancer, ovarian cancer, or otherhormone-sensitive cancer (e.g., cancer sensitive to estrogen orprogesterone); and are suitable for use in treating subjects sufferingfrom other diseases, disorders, or syndromes.

In embodiments of the methods disclosed herein, a patient currentlyreceiving a GRM, such as mifepristone, is also concomitantlyadministered a steroidogenesis inhibitor or a CYP3A inhibitor such asketoconazole or itraconazole. In embodiments of the methods disclosedherein, a patient currently receiving a GRM, such as mifepristone, astreatment for a condition characterized by excess steroid levels, or astreatment of a condition that is treated by reducing steroid levels orby reducing steroid effects, is also concomitantly administered asteroidogenesis inhibitor or a CYP3A inhibitor such as ketoconazole oritraconazole, whereby the patient is treated for that condition. Inembodiments, the condition is characterized by excessive cortisollevels. In embodiments, the condition is hyperglycemia secondary tohypercortisolism, e.g., in a patient suffering from endogenous Cushing'ssyndrome. In embodiments, the condition is cancer, and may be ahormone-sensitive cancer. In embodiments, the hormone sensitive canceris prostate cancer, breast cancer, or ovarian cancer.

In embodiments of the methods disclosed herein, a patient currentlyreceiving a steroidogenesis or a CYP3A inhibitor such as ketoconazole oritraconazole is also concomitantly administered a GRM. In embodiments ofthe methods disclosed herein, a patient currently receiving asteroidogenesis or a CYP3A inhibitor such as ketoconazole oritraconazole as treatment for a condition characterized by excesssteroid levels, or as treatment of a condition that is treated byreducing steroid levels or by reducing steroid effects, is alsoconcomitantly administered a GRM, whereby the patient is treated forthat condition. In embodiments, the condition is characterized byexcessive cortisol levels. In embodiments, the condition ishyperglycemia secondary to hypercortisolism, e.g., in a patientsuffering from endogenous Cushing's syndrome. In embodiments, thecondition is hyperglycemia secondary to hypercortisolism, e.g., in apatient suffering from endogenous Cushing's syndrome. In embodiments,the condition is cancer, and may be a hormone-sensitive cancer. Inembodiments, the hormone sensitive cancer is prostate cancer, breastcancer, or ovarian cancer.

Thus, in embodiments of the methods disclosed herein, a patient in needof treatment for a condition is concomitantly administered both a GRM(such as mifepristone) and a steroidogenesis or a CYP3A inhibitor (suchas ketoconazole or itraconazole), whereby the patient is treated forthat condition. In embodiments, the condition is characterized byexcessive cortisol levels. In embodiments, the condition ishyperglycemia secondary to hypercortisolism, e.g., in a patientsuffering from endogenous Cushing's syndrome. In embodiments, thecondition is cancer, and may be a hormone-sensitive cancer. Inembodiments, the hormone sensitive cancer is prostate cancer, breastcancer, or ovarian cancer.

In embodiments, the amount of GRM administered concomitantly with asteroidogenesis or a CYP3A inhibitor is the same amount, orsubstantially the same amount, of GRM previously administered to thepatient prior to concomitant administration of a GRM and asteroidogenesis or a CYP3A inhibitor. In embodiments, the amount of GRMadministered concomitantly with a steroidogenesis or a CYP3A inhibitoris less than the amount of GRM previously administered to the subjectprior to concomitant administration of a GRM and a steroidogenesis or aCYP3A inhibitor. In embodiments, administration of a reduced amount ofGRM administered concomitantly with a steroidogenesis or a CYP3Ainhibitor is an effective amount of GRM; in embodiments, the reducedamount of GRM administered concomitantly with a steroidogenesis or aCYP3A inhibitor is as effective as the amount of GRM previouslyadministered to the subject prior to concomitant administration of a GRMand a steroidogenesis or a CYP3A inhibitor. The GRM may be mifepristone.The steroidogenesis or a CYP3A inhibitor may be ketoconazole.

In embodiments, the amount of steroidogenesis or a CYP3A inhibitoradministered concomitantly with the GRM is the same amount, orsubstantially the same amount, of steroidogenesis or CYP3A inhibitorpreviously administered to the subject prior to concomitantadministration of a GRM and a steroidogenesis or a CYP3A inhibitor. Inembodiments, the amount of steroidogenesis or CYP3A inhibitoradministered concomitantly with the GRM is less than the amount ofsteroidogenesis or CYP3A inhibitor previously administered to thesubject prior to concomitant administration of a GRM and asteroidogenesis or a CYP3A inhibitor. In embodiments, administration ofa reduced amount of steroidogenesis or CYP3A inhibitor administeredconcomitantly with a GRM is an effective amount of steroidogenesis orCYP3A inhibitor; in embodiments, the reduced amount of steroidogenesisor CYP3A inhibitor administered concomitantly with a GRM is as effectiveas the amount of steroidogenesis or CYP3A inhibitor previouslyadministered to the subject prior to concomitant administration of a GRMand a steroidogenesis or a CYP3A inhibitor. The GRM may be mifepristone.The steroidogenesis or CYP3A inhibitor may be ketoconazole.

Concomitant administration of a GRM and steroidogenesis or a CYP3Ainhibitor may be administration of a GRM followed within a short time byadministration of a steroidogenesis or a CYP3A inhibitor. Inembodiments, concomitant administration of a GRM and a steroidogenesisor a CYP3A inhibitor may be administration of mifepristone followedwithin a short time by administration of ketoconazole. Concomitantadministration of a GRM and a steroidogenesis or a CYP3A inhibitor maybe administration of a steroidogenesis or a CYP3A inhibitor followedwithin a short time by administration of a GRM. In embodiments,concomitant administration of a GRM and a steroidogenesis or a CYP3Ainhibitor may be administration of ketoconazole followed within a shorttime by administration of mifepristone. Concomitant administration of aGRM and a steroidogenesis or a CYP3A inhibitor may be simultaneousadministration of a GRM and a steroidogenesis or a CYP3A inhibitor. Inembodiments, concomitant administration of a GRM and a steroidogenesisor a CYP3A inhibitor may be simultaneous administration of mifepristoneand ketoconazole.

In embodiments, the GRM is a steroidal GRM, such as, e.g., mifepristone.In embodiments, the GRM is a non-steroidal GRM. In embodiments, the GRMis a glucocorticoid receptor antagonist (GRA). In embodiments, the GRAis a steroidal GRA. In embodiments, the GRA is mifepristone. Inembodiments, the GRA is a non-steroidal GRA. In embodiments, the GRA isa non-steroidal GRA selected from a GRA having a cyclohexyl-pyrimidinebackbone, GRA having a fused azadecalin backbone, a GRA having aheteroaryl ketone fused azadecalin backbone, and a GRA having anoctahydro fused azadecalin backbone.

In embodiments, a patient is concomitantly administered a GRM andketoconazole; in embodiments, the GRM is mifepristone. In embodiments,concomitant administration comprises simultaneous administration of aGRM and ketoconazole to a patient, where the GRM is mifepristone. Inembodiments, the amount of ketoconazole administered concomitantly withthe mifepristone is the same amount, or substantially the same amount,of ketoconazole previously administered to the subject prior toconcomitant administration of mifepristone and ketoconazole. Inembodiments, the amount of ketoconazole administered concomitantly withthe mifepristone is less than the amount of ketoconazole previouslyadministered to the subject prior to concomitant administration ofmifepristone and ketoconazole.

Accordingly, in embodiments, Applicant discloses herein a method fortreating a patient who is suffering from Cushing's syndrome or acondition associated with Cushing's syndrome, said patient receiving afirst dose of a GRM, such as a glucocorticoid receptor antagonist (GRA),said method comprising: concomitantly administering to the patient adose of a CYP3A inhibitor and a reduced dose of said GRM, wherein saidreduced GRM dose consists of a GRM dose that is less than the first GRMdose, whereby the patient is treated for Cushing's syndrome or acondition associated with Cushing's syndrome by concomitantadministration of said CYP3A inhibitor and a reduced dose said GRM.Conditions associated with Cushing's syndrome include, withoutlimitation, hyperglycemia secondary to hypercortisolism, e.g.,hyperglycemia secondary to hypercortisolism in a patient suffering fromendogenous Cushing' syndrome. Conditions associated with Cushing'ssyndrome also include, without limitation, hyperglycemia secondary tohypercortisolism in an adult Cushing's syndrome patient who has type 2diabetes mellitus or glucose intolerance. Conditions associated withCushing's syndrome further include, without limitation, hyperglycemiasecondary to hypercortisolism in an adult Cushing's syndrome patient whohas a) type 2 diabetes mellitus or glucose intolerance, and b) hasfailed surgery or is not a candidate for surgery.

In embodiments, the dosage of said reduced GRM dose is less than thedosage of said first GRA dose by at least an amount selected from about5%, 10%, 15%, 20%, 25%, 30%, 33^(1/3)% 35%, 40%, 45%, 50%, 55%, 60%, 65%66^(2/3)% 70%, 75%, 80%, 85%, and 90% of the first GRM dose. Inembodiments, the dosage of said reduced GRM dose is less than the dosageof said first GRM dose by about 300 milligrams (mg) of said GRM. Inembodiments, the dosage amount of said first GRM dose is 600 mg orhigher of said GRM. In embodiments, said reduced GRM dose is a GRM doseselected from the group of GRM doses consisting of about 1500 milligrams(mg) GRM, about 1200 mg GRA, about 900 mg GRM, and about 600 mg GRM. Inembodiments, said reduced GRM dose is 900 mg of the GRM. In embodiments,said reduced GRM dose is 600 mg of the GRM. In embodiments, the reducedGRM dose is a daily GRM dose. In embodiments, the methods furthercomprise titrating upwards the dosage of the reduced GRM dose. Inembodiments, such titrating upwards comprises increasing the dosage ofthe reduced GRM dose in increments of 300 milligrams (mg) of GRM. Inembodiments, the interval of time between upward titration of a reduceddose, or of an upwardly titrated reduced dose, and a subsequent upwardtitration of a dosage of the reduced dose of mifepristone is selectedfrom one week, two weeks, three weeks, and four weeks. In embodiments,the methods include monitoring the patient for clinical response to theGRM. In embodiments, such titrating upwards follows a determination thatsaid reduced GRM dose is associated with a decrease in clinical responseto the GRM. In embodiments, monitoring the patient for clinical responseto the GRM comprises monitoring the patient for glucose control,anti-diabetic medication requirement, insulin level, psychiatricsymptoms, cushingoid appearance, acne, hirsutism, body weight, orcombinations thereof. In embodiments, such titrating upwards is cappedat a dosage level of 900 milligrams per day. In embodiments, suchtitrating upwards is capped at a dosage level of 600 milligrams per day.In embodiments of the methods disclosed herein, the reduced GRM dose isa daily dose of 900 mg mifepristone. In embodiments of the methodsdisclosed herein, the reduced GRM dose is a daily dose of 600 mgmifepristone.

Embodiments of the methods disclosed herein are directed to treating apatient suffering from Cushing's syndrome or a condition associated withCushing's syndrome. In embodiments, the patient suffering from Cushing'ssyndrome or a condition associated with Cushing's syndrome is a patientsuffering from a condition associated with endogenous Cushing'ssyndrome. In embodiments, treating a patient who is suffering fromCushing's syndrome or a condition associated with Cushing's syndromecomprises treating a patient who is suffering from hyperglycemiasecondary to hypercortisolism. In embodiments, treating patient who issuffering from Cushing's syndrome or a condition associated withCushing's syndrome comprises treating hyperglycemia secondary tohypercortisolism in a Cushing's syndrome patient having type 2 diabetesmellitus or glucose intolerance. In embodiments, treating a patient whois suffering from Cushing's syndrome or a condition associated withCushing's syndrome comprises treating hyperglycemia secondary tohypercortisolism in a Cushing's syndrome patient, said patient a) havingtype 2 diabetes mellitus or glucose intolerance, and b) having failedsurgery or is not a candidate for surgery. In embodiments, treating apatient who is suffering from Cushing's syndrome or a conditionassociated with Cushing's syndrome comprises administering mifepristoneto control hyperglycemia secondary to hypercortisolism in an adultCushing's syndrome patient who has a) type 2 diabetes mellitus orglucose intolerance, and b) has failed surgery or is not a candidate forsurgery.

In embodiments, Applicant discloses herein a method for treating apatient who is suffering from Cushing's syndrome or a conditionassociated with Cushing's syndrome, said patient receiving a first doseof a glucocorticoid receptor modulator (GRM), such as a glucocorticoidreceptor antagonist (GRA), said method comprising: concomitantlyadministering to the patient a dose of said CYP3A inhibitor and a firstdose of a glucocorticoid receptor modulator (GRM), whereby the patientis treated for Cushing's syndrome or a condition associated withCushing's syndrome by concomitant administration of said CYP3A inhibitorand said GRM. In embodiments, the first GRM dose is selected from a GRMdose no greater than 900 milligrams (mg) per day of the GRM, and nogreater than 600 mg per day of the GRM. In embodiments, the patient hadbeen administered a dose of the CYP3A inhibitor prior to saidadministering of said first GRM dose. In embodiments, said concomitantadministration of the CYP3A inhibitor and said GRM comprisesadministration of said first GRM dose to a patient having detectablelevels of said CYP3A inhibitor, wherein said patient had beenadministered a dose of the CYP3A inhibitor prior to said administrationof said first GRM dose. In embodiments, methods further comprisetitrating upwards the dosage of a subsequent GRM dose, wherein thedosage of said subsequent GRM dose is a greater amount of GRM than theamount of GRM of the first GRM dose. In embodiments, such titratingupwards comprises increasing the dosage of the subsequent GRM dose inincrements of 300 milligrams (mg) of GRM. In embodiments, the intervalof time between upward titration of a subsequent GRM dose, or of anupwardly titrated subsequent GRM dose, and a subsequent upward titrationof the dosage of the subsequent GRM dose is selected from one week, twoweeks, three weeks, and four weeks.

In embodiments, Applicant discloses herein the use of a glucocorticoidreceptor modulator (GRM) when the patient is receiving concomitantadministration of a CYP3A inhibitor to treat a patient who is sufferingfrom Cushing's syndrome or a condition associated with Cushing'ssyndrome. In embodiments, Applicant discloses herein the use of a GRMwhen the patient is receiving concomitant administration of a CYP3Ainhibitor to control hyperglycemia secondary to hypercortisolism in apatient with endogenous Cushing's syndrome. In embodiments of such uses,the GRM is mifepristone. In embodiments of such uses, the CYP3Ainhibitor is ketoconazole or itraconazole. In embodiments of such uses,the use comprises a once-daily dose of said GRM. In embodiments of suchuses, the once-daily dose of said GRM is titrated up to greater than 800mg per day from 300 mg per day or 600 mg per day of GRM.

In embodiments of the methods and uses disclosed herein, the CYP3Ainhibitor is a strong CYP3A inhibitor selected from the group consistingof ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir,indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin,conivaptan, lopinavir/ritonavir, posaconazole, saquinavir,telithromycin, and voriconazole. In embodiments, the CYP3A inhibitor isketoconazole or itraconazole.

In embodiments of the methods and uses disclosed herein, the GRM ismifepristone.

The methods and uses disclosed herein provide advantages includingexpanded treatment options for patients suffering from conditionsincluding Cushing's syndrome, Cushing's Disease, prostate cancer, breastcancer, ovarian cancer, and other conditions.

The methods and uses disclosed herein provide advantages includingimproved treatments for patients suffering from conditions includingCushing's syndrome, Cushing's Disease, prostate cancer, breast cancer,ovarian cancer, and other conditions, where such improved treatments mayinclude the ability to alter the amount of a GRM, such mifepristone,administered to the patient by administering a GRM such as mifepristoneconcomitantly with ketoconazole. In embodiments, such improvedtreatments include the ability to reduce the amount of a GRM, such asmifepristone, administered to a subject.

The methods and uses disclosed herein provide advantages includingimproved treatments for patients suffering from conditions includingCushing's syndrome, Cushing's Disease, prostate cancer, breast cancer,ovarian cancer, and other conditions, where such improved treatments mayinclude the ability to alter the amount of a CYP3A inhibitor such asketoconazole or itraconazole administered to the patient byadministering a GRM such as mifepristone concomitantly with the CYP3Ainhibitor. In embodiments, such improved treatments include the abilityto reduce the amount of the CYP3A inhibitor administered to a subjectand thus to reduce risk of toxic effects of a CYP3A inhibitor, such as,e.g., ketoconazole or itraconazole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean and standard deviation of mifepristone and itsmetabolites RU42633, RU42698, and RU42848 measured in healthy malevolunteers prior to administration of mifepristone on days one throughseventeen. Ketoconazole was also administered on daysthirteen-seventeen.

FIG. 2 shows the plasma concentration profile of mifepristone measuredin healthy male volunteers on day twelve (before administration ofketoconazole) and on day seventeen (the fifth day of ketoconazoleadministration).

FIG. 3 shows the plasma concentration profile of mifepristone measuredin healthy male volunteers over the course of twenty four hours sincedosing on day 14 of the study (administration of 1200 mg mifepristoneonce-per-day; triangles); on study day 28 (administration of 900 mgmifepristone once-per-day; circles); and on study day 42 (administrationof 900 mg mifepristone once-per-day and of 200 mg itraconazoleonce-per-day; squares).

DETAILED DESCRIPTION

Ketoconazole strongly inhibits corticosteroid synthesis; thus,ketoconazole strongly reduces cortisol levels in subjects administeredketoconazole. However, there is concern over its use, for example, dueto potential hepatoxicity (see, e.g., Castinetti et al., J ClinEndocrinol Metab 99(5):1623-1630 (2014)).

According to the U.S. Food and Drug Administration (FDA) definition(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm, accessed Feb. 16, 2017), strong CYP3Ainhibitors are expected to increase the AUC of other drugs by greaterthan five-fold. Ketoconazole is identified by the FDA as a strong CYP3Ainhibitor.

Surprisingly, as disclosed herein, concomitant administration ofmifepristone and ketoconazole causes only a small increase in the plasmalevels of mifepristone, and does not cause the large increases thatwould have been expected for such concomitant administration.

Applicant has surprisingly found that concomitant administration ofmifepristone and ketoconazole causes only a small increase in the AUCand in the C_(max) of mifepristone in subjects receiving mifepristonealone for twelve days, and then administered both mifepristone andketoconazole concomitantly. The C_(max) of mifepristone administeredconcomitantly with ketoconazole is increased by less than two-fold (amere 28% increase in mifepristone C_(max)) and the AUC of mifepristoneadministered concomitantly with ketoconazole is increased by less thantwo-fold (a mere 38% increase in mifepristone AUC) in subjects receiving600 mg mifepristone per day who then are given 400 mg ketoconazole (200mg twice per day)).

Also surprisingly, as disclosed herein, concomitant administration ofketoconazole and mifepristone also caused smaller increases inketoconazole levels than would be expected. The C_(max) of ketoconazoleadministered concomitantly with mifepristone is increased by less thanfour-fold (365% increase in ketoconazole C_(max)) and the AUC ofketoconazole administered concomitantly with mifepristone is increasedby less than three-fold (253% increase in ketoconazole AUC) whencomparing ketoconazole levels on the first day of concomitantadministration of both drugs as compared to the ketoconazole levels insubjects on the fifth day of receiving 400 mg ketoconazole (200 mg twiceper day) concomitantly with 600 mg mifepristone per day.

Applicant has surprisingly found that concomitant administration ofmifepristone and itraconazole causes only a small increase in the AUCand in the C_(max) of mifepristone in subjects receiving mifepristonealone, and then administered both mifepristone and itraconazoleconcomitantly. Administration of itraconazole (200 mg once per daywithin 30 minutes after breakfast) with mifepristone (900 mg once perday, within 5 minutes following itraconazole) led to mifepristone levelsin subjects comparable to those levels obtained in the subjects when1200 mg mifepristone was given alone (within 30 minutes afterbreakfast). The C_(max) of 900 mg mifepristone per day administeredconcomitantly with 200 mg itraconazole per day is increased by about 20%as compared to the C_(max) of 900 mg mifepristone per day administeredwithout itraconazole; the AUC₀₋₂₄ of 900 mg mifepristone per dayadministered concomitantly with 200 mg itraconazole per day is increasedby about 10% as compared to the AUC₀₋₂₄ of 900 mg mifepristone per dayadministered without itraconazole.

Ketoconazole is a strong inhibitor of steroidogenesis; thus it isbelieved that ketoconazole may serve as an exemplar for other stronginhibitors of steroidogenesis and that these results indicate thatmifepristone, and other glucocorticoid receptor modulators, includingother glucocorticoid receptor antagonists, may be safely administeredconcomitantly with steroidogenesis inhibitors according to the methodsdisclosed herein.

Applicant discloses herein methods for the safe concomitantadministration of both a glucocorticoid receptor modulator (GRM) andsteroidogenesis inhibitor to a subject. Applicant discloses herein thesurprising finding that both a GRM such as mifepristone and asteroidogenesis inhibitor such as ketoconazole may be safelyadministered to a subject at the same, or nearly the same, time (i.e.,the GRM and the steroidogenesis inhibitor may be concomitantlyadministered).

Applicant discloses herein methods for the safe concomitantadministration of both a glucocorticoid receptor modulator (GRM) andCYP3A inhibitor to a subject. Applicant discloses herein the surprisingfinding that both a GRM such as mifepristone and a CYP3A inhibitors suchas ketoconazole and itraconazole may be safely administered to a subjectat the same, or nearly the same, time (i.e., the GRM and the CYP3A maybe concomitantly administered).

Applicant discloses herein surprising results showing the safeconcomitant administration of mifepristone, a glucocorticoid receptormodulator, and ketoconazole or itraconazole. Ketoconazole anditraconazole are strong inhibitors of CYP3A enzymes, and may be used todetermine the effects of the class of strong CYP3A inhibitors (see FDA“Clinical Drug Interaction Studies—Study Design, Data Analysis, andClinical Implications Guidance for Industry”, pages 10-11(https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf). Thus itis believed that ketoconazole and itraconazole may serve as examplarsfor other strong inhibitors of CYP3A enzymes. The results withmifepristone disclosed herein are believed to indicate that mifepristoneand also other glucocorticoid receptor modulators, including otherglucocorticoid receptor antagonists, may be safely administeredconcomitantly with CYP3A enzyme inhibitors according to the methodsdisclosed herein. Such CYP3A enzyme inhibitors include strong CYP3Ainhibitors (such as, e.g., ketoconazole, itraconazole, nefazodone,ritonavir, nelfinavir, indinavir, atazanavir, amprenavir andfosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir,posaconazole, saquinavir, telithromycin, and voriconazole). Since lessstrong CYP3A inhibitors would be expected to have smaller effects onplasma levels of mifepristone and its metabolites, these resultsindicate that mifepristone may also be safely administered with otherCYP3A inhibitors in addition to those listed above, including CYP3Ainhibitors that are not strong CYP3A inhibitors (such as, e.g.,fluconazole, cimetidine, boceprevir, and telaprevir).

Applicant discloses herein the surprising finding that a subjectreceiving the CYP3A inhibitor ketoconazole or the CYP3A inhibitoritraconazole, may also be safely administered an effective dose ofmifepristone, which is a glucocorticoid receptor modulator (GRM), e.g.,a glucocorticoid receptor antagonist (GRA). Applicant also disclosesherein the surprising finding that a subject receiving mifepristone,which is a GRM, e.g., a GRA, may also be safely administered the CYP3Ainhibitor ketoconazole or the CYP3A inhibitor itraconazole. Applicantalso discloses herein the surprising finding that a subject receivingmifepristone may also be safely administered a steroidogenesis inhibitor(i.e., ketoconazole); ketoconazole is a steroidogenesis inhibitor inaddition to being a CYP3A inhibitor.

In embodiments of the methods disclosed herein, a subject receiving aGRM (such as, e.g., a GRA such as mifepristone) may be safelyadministered an effective dose of a steroidogenesis inhibitor such asketoconazole. In embodiments of the methods disclosed herein, a subjectmay be safely administered ketoconazole and a reduced dose of a GRM,where the reduced dose of a GRM is an effective dose of GRM that is asmaller GRM dose than the GRM dose administered in the absence of asteroidogenesis inhibitor such as ketoconazole. In embodiments of themethods disclosed herein, a subject may be safely administered a GRM anda reduced dose of a steroidogenesis inhibitor such as ketoconazole,where the reduced dose of the steroidogenesis inhibitor is an effectivedose of the steroidogenesis inhibitor that is a smaller dose than the asteroidogenesis inhibitor dose administered in the absence of the GRM.In embodiments of the methods disclosed herein, a subject receiving asteroidogenesis inhibitor such as, e.g., ketoconazole, may be safelyadministered an effective dose of a GRM, such as, e.g., mifepristone. Inembodiments of the methods disclosed herein, a subject receiving a GRM,such as, e.g., mifepristone, may be safely administered an effectivedose of a steroidogenesis inhibitor such as, e.g., ketoconazole.

These methods may be applied to subjects suffering from diseases ordisorders as well as other subjects, including subjects suffering fromCushing's syndrome. Such concomitant administration of a steroidogenesisinhibitor such as ketoconazole with a GRM would have been expected toproduce toxic side effects due to, e.g., an adverse effect onsteroidogenesis inhibitor metabolism due to the added GRM (e.g., wherethe steroidogenesis inhibitor is ketoconazole, a previously safeketoconazole dose would have been expected to be a toxic dose in thepresence of added GRM (e.g., mifepristone)).

In particular, Applicant discloses herein that patients suffering from adisease or disorder and receiving ketoconazole or itraconazole may besafely administered mifepristone concomitantly with the administrationof ketoconazole or itraconazole. Such concomitant administration ofmifepristone with ketoconazole or itraconazole surprisingly does notincrease the risk of toxicity in the patient, and is believed to be safefor the patient. In particular, Applicant discloses herein thatCushing's syndrome patients receiving ketoconazole or itraconazole maybe safely administered mifepristone concomitantly with theadministration of ketoconazole or itraconazole. Such concomitantadministration of ketoconazole or itraconazole with mifepristonesurprisingly does not increase the risk of toxicity in humans, and isbelieved to be safe for a patient suffering from Cushing's syndrome.

Thus, Applicant discloses herein surprising and useful methods forconcomitant administration of a CYP3A inhibitor such as, e.g.,ketoconazole or itraconazole, and a GRM such as, e.g., mifepristone,which provide the benefits of improved treatment without substantiallyincreased risk of adverse treatment side-effects. For example, Applicantprovides herein surprising and useful methods for concomitantadministration of ketoconazole or itraconazole with mifepristone, whichprovide the benefits of both drugs without substantially increased riskof ketoconazole or itraconazole toxicity, which can have serious adverseeffects on the liver.

Thus, Applicant discloses herein surprising and useful methods forconcomitant administration of a steroidogenesis inhibitor such as, e.g.,ketoconazole, and a GRM such as, e.g., mifepristone, which provide thebenefits of improved treatment without substantially increased risk ofadverse treatment side-effects. For example, Applicant provides hereinsurprising and useful methods for concomitant administration ofketoconazole and mifepristone, which provide the benefits of both drugswithout substantially increased risk of ketoconazole toxicity, which canhave serious adverse effects on the liver.

Thus, contrary to the expectation that the presence of a GRM such asmifepristone along with a steroidogenesis inhibitor (e.g., ketoconazole)in a patient would increase the toxicity of the steroidogenesisinhibitor beyond that expected for such a dose of steroidogenesisinhibitor alone, Applicant has discovered that administering a) both aGRM (e.g., mifepristone) and a steroidogenesis inhibitor (e.g.,ketoconazole) to a subject, or b) administering a GRM (e.g.,mifepristone) to a subject who has recently been given a steroidogenesisinhibitor (e.g., ketoconazole), or c) administering a steroidogenesisinhibitor (e.g., ketoconazole) soon after GRM (e.g., mifepristone)administration to a subject, concomitant administration of a GRM and asteroidogenesis inhibitor does not increase the expected toxicity of thesteroidogenesis inhibitor. In embodiments, concomitant administration ofa steroidogenesis inhibitor and a GRM allows for administration of aneffective dose of GRM that is a reduced GRM dose as compared to the GRMdose administered in the absence of the steroidogenesis inhibitor.

In embodiments, concomitant administration of ketoconazole andmifepristone allows for administration of an effective dose ofmifepristone that is a reduced dose of mifepristone as compared to themifepristone dose administered in the absence of ketoconazole. Forexample, Applicant has discovered that concomitant administration ofmifepristone and ketoconazole makes it possible to reduce the dose ofmifepristone while maintaining sufficient mifepristone levels foreffective therapy for the patient. Such a reduction in mifepristone doseprovides the benefit of reducing the amount of mifepristone administeredto the subject. Embodiments in which a subject is concomitantlyadministered ketoconazole and mifepristone allow for mifepristone dosereduction (as compared to the mifepristone dose in the absence ofketoconazole) include, e.g., Cushing's syndrome and hormone-sensitivecancers such as breast, ovarian, and prostate cancer, and otherdisorders susceptible of treatment by mifepristone.

In embodiments, the reduced dose of mifepristone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is at least about 5% less than the original dose ofmifepristone, where the original dose of mifepristone is the dose thesubject had been, or would have been, administered in the absence ofketoconazole co-administration. In embodiments, the reduced dose ofmifepristone is a dose of mifepristone that is at least about 10% lessthan the original dose of mifepristone; and may be a dose ofmifepristone that is at least about 15%, or about 20%, or about 22%, orabout 23%, or about 25%, or about 28%, or about 29%, or about 33%, orabout 38%, or about 40%, or about 50%, or about 66%, or about 75% lessthan the original dose of mifepristone.

In embodiments, the reduced dose of mifepristone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is 300 mg less mifepristone than the amount of theoriginal dose of mifepristone. In embodiments, the reduced dose ofmifepristone administered to a subject also concomitantly receivingketoconazole is a dose of mifepristone that is an amount of mifepristonethat is an integer multiple of 300 mg mifepristone less than the amountof the original dose of mifepristone. In embodiments, the integer of theinteger multiple is selected from the integers 1, 2, 3, 4, and 5.

In embodiments, the reduced dose of mifepristone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is about 900 mg mifepristone; or is about 600 mgmifepristone; or is about 300 mg mifepristone. In embodiments, thereduced dose of mifepristone administered to a subject alsoconcomitantly receiving ketoconazole is a dose of mifepristone that isabout 300 mg mifepristone administered only every other day; or is about300 mg mifepristone administered every third day; or is about 300 mgmifepristone administered every fourth day. For example, where theoriginal dose of mifepristone is about 1500 mg per day, the reduced doseof mifepristone may be about 1200 mg of mifepristone administered everyday; or may be about 900 mg of mifepristone administered every day; ormay be about 600 mg of mifepristone administered every day; or may beabout 300 mg of mifepristone administered every day. For example, wherethe original dose of mifepristone is about 1200 mg per day, the reduceddose of mifepristone may be about 900 mg of mifepristone administeredevery day; or may be about 600 mg of mifepristone administered everyday; or may be about 300 mg of mifepristone administered every day. Forexample, where the original dose of mifepristone is about 900 mg perday, the reduced dose of mifepristone may be about 600 mg ofmifepristone administered every day; or may be about 300 mg ofmifepristone administered every day; or may be about 300 mg ofmifepristone administered every other day. For example, where theoriginal dose of mifepristone is about 600 mg per day, the reduced doseof mifepristone may be about 300 mg of mifepristone administered everyday; or may be about 300 mg of mifepristone administered every otherday; or may be about 300 mg of mifepristone administered every thirdday. For example, where the original dose of mifepristone is about 300mg per day, the reduced dose of mifepristone may be about 300 mg ofmifepristone administered every other day; or may be about 300 mg ofmifepristone administered every third day; or may be about 300 mg ofmifepristone administered every fourth day.

In embodiments in which a subject has been receiving about 1800 mgmifepristone per day, and concomitant administration of mifepristone anda CYP3A inhibitor such as, e.g., ketoconazole or itraconazole, isindicated, the reduced dose of mifepristone may be about 1500 mgmifepristone per day; may be about 1200 mg mifepristone per day; may beabout 900 mg mifepristone per day; may be greater than 800 mg/day; maybe about 600 mg mifepristone per day; may be about 300 mg mifepristoneper day; may be about 300 mg mifepristone every other day; or may beabout 300 mg mifepristone every third day. In embodiments in which asubject has been receiving about 1500 mg mifepristone per day, andconcomitant administration of mifepristone and a CYP3A inhibitor suchas, e.g., ketoconazole or itraconazole, is indicated, the reduced doseof mifepristone may be about 1200 mg mifepristone per day; may be about900 mg mifepristone per day; may be greater than 800 mg/day; may beabout 600 mg mifepristone per day; may be about 300 mg mifepristone perday; may be about 300 mg mifepristone every other day; or may be about300 mg mifepristone every third day. In embodiments in which a subjecthas been receiving about 1200 mg mifepristone per day, and concomitantadministration of mifepristone and a CYP3A inhibitor such as, e.g.,ketoconazole or itraconazole, is indicated, the reduced dose ofmifepristone may be about 900 mg mifepristone per day; may be greaterthan 800 mg/day; may be about 600 mg mifepristone per day; may be about300 mg mifepristone per day; may be about 300 mg mifepristone everyother day; or may be about 300 mg mifepristone every third day. Inembodiments in which a subject has been receiving about 900 mgmifepristone per day, and concomitant administration of mifepristone anda CYP3A inhibitor such as, e.g., ketoconazole or itraconazole, isindicated, the reduced dose of mifepristone may be greater than 800mg/day; may be about 600 mg mifepristone per day; may be about 300 mgmifepristone per day; may be about 300 mg mifepristone every other day;or may be about 300 mg mifepristone every third day. In embodiments inwhich a subject has been receiving about 600 mg mifepristone per day,and concomitant administration of mifepristone and a CYP3A inhibitorsuch as, e.g., ketoconazole or itraconazole, is indicated, the reduceddose of mifepristone may be about 300 mg mifepristone per day; may beabout 300 mg mifepristone every other day; may be about 300 mg everythird day; or may be about 300 mg mifepristone every fourth day. Inembodiments in which a subject has been receiving about 300 mgmifepristone per day, and concomitant administration of mifepristone anda CYP3A inhibitor such as, e.g., ketoconazole or itraconazole, isindicated, the reduced dose of mifepristone may be about 300 mgmifepristone every other day; may be about 300 mg every third day; ormay be about 300 mg mifepristone every fourth day.

In embodiments in which a subject has been receiving a first dose ofmifepristone (e.g. a daily dose of mifepristone of about 1800 mg/day, orabout 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, or greaterthan 800 mg/day, or about 600 mg/day, or about 300 mg/day), andconcomitant administration of mifepristone and a CYP3A inhibitor suchas, e.g., ketoconazole or itraconazole, is indicated, the subject may beadministered a reduced dose of mifepristone, where the amount of thereduced dose is less than the original mifepristone dose by about 300 mgmifepristone per day, and the subject may be monitored for clinicaleffects of the drugs, including monitoring for clinical response tomifepristone. In embodiments in which a subject has been receiving afirst dose of mifepristone (e.g. a daily dose of mifepristone of about1800 mg/day, or about 1500 mg/day, or about 1200 mg/day, or about 900mg/day, or greater than 800 mg/day, or about 600 mg/day, or about 300mg/day), and concomitant administration of mifepristone and a CYP3Ainhibitor such as, e.g., ketoconazole or itraconazole, is indicated, thesubject may be administered a reduced dose of mifepristone, where theamount of the reduced dose is less than the original mifepristone doseby about 300 mg mifepristone per day, and the reduced dose ofmifepristone may be subsequently titrated upwards (i.e., increased insubsequent dose administrations) in increments of about 300 mgmifepristone. In embodiments, such upward titration of the reduced dosein increments of 300 mg/day may be subjected to a maximum daily dosageof about 600 mg/day, or greater than 800 mg/day, or of about 900 mg/day,or of about 1200 mg/day, or of about 1500 mg/day. In embodiments, suchupward titration of the dosage of the reduced daily dose of mifepristoneadministered per day is capped at a maximum daily dose, wherein saidmaximum daily dose is selected from the group consisting of 900milligrams (mg) mifepristone per day, greater than 800 mg mifepristoneper day, and 600 mg mifepristone per day.

The subject may be monitored for clinical effects of the drugs, e.g.,for clinical response to the GRM (e.g., mifepristone), adverse events,side-effects of any drug, at any stage or at all stages, of suchincremental upward titration of the mifepristone dosage. The interval oftime between administration of a reduced dose, or of an upwardlytitrated reduced dose, and an upward titration of a dose of mifepristonemay be an interval selected from two days, four days, one week, twoweeks, one month, two months, and three months. In embodiments, theinterval of time between upward titration of a reduced dose, or of anupwardly titrated reduced dose, and a subsequent upward titration of adosage of the reduced dose of mifepristone is selected from one week,two weeks, three weeks, and four weeks. Monitoring the patient forclinical response may include monitoring the patient (e.g., to identifyor determine if there are changes in) for glucose control, anti-diabeticmedication requirement, insulin level, psychiatric symptoms, cushingoidappearance, acne, hirsutism, and monitoring the body weight of thepatient (e.g., to identify or determine if there are changes in any oneor more of these symptoms and characteristics).

In embodiments in which a subject has been receiving a first dose ofmifepristone (e.g. a daily dose of mifepristone of about 1800 mg/day, orabout 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, or greaterthan 800 mg/day, or about 600 mg/day, or about 300 mg/day), andconcomitant administration of mifepristone and a CYP3A inhibitor suchas, e.g., ketoconazole or itraconazole, is indicated, the subject may beadministered a reduced dose of mifepristone, where the amount of thereduced dose is less than the original mifepristone dose, and thereduced dose of mifepristone may be about 1500 mg mifepristone per day,or about 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, orgreater than 800 mg/day, or about 600 mg/day, or about 300 mg/day; andthe subject may be monitored for clinical response to the GRM, or forother clinical effects of the drugs. In such embodiments, the reduceddose of mifepristone may be subsequently titrated upwards (i.e.,increased in subsequent dose administrations) in increments of about 300mg mifepristone. In embodiments, such upward titration of the reduceddose in increments of 300 mg/day may be subjected to a maximum dailydosage of about 600 mg/day, or greater than 800 mg/day, or of about 900mg/day, or of about 1200 mg/day, or of about 1500 mg/day. Inembodiments, such upward titration of the dosage of the reduced dailydose of mifepristone administered per day is capped at a maximum dailydose, wherein said maximum daily dose is selected from the groupconsisting of 900 milligrams (mg) mifepristone per day, greater than 800mg mifepristone per day, and 600 mg mifepristone per day.

The subject may be monitored for clinical response to the drugs,including e.g., clinical response to the GRM (e.g., mifepristone), foradverse events, side-effects of any of the drugs, at any stage, or atall stages, of such incremental upward titration of the mifepristonedosage. Upward titration of a reduced dose of mifepristone may beperformed every two days, or every four days, or every week, or everytwo weeks, or every month, or every two months. In embodiments, theinterval of time between upward titration of a reduced dose, or of anupwardly titrated reduced dose, and a subsequent upward titration of adosage of the reduced dose of mifepristone is selected from one week,two weeks, three weeks, and four weeks.

Applicant discloses herein that concomitant treatment with bothmifepristone and ketoconazole, and concomitant treatment with bothmifepristone and itraconazole, may lead to small increases in plasmalevels of mifepristone as measured by C_(max) and as measured by AUC.For example, as disclosed in Table 3 below, concomitant administrationof mifepristone and ketoconazole led to about 28% (27.59%, or about 30%)increase in mifepristone C_(max) and about 38% (38.01%, about 40%)increase in mifepristone AUC. Thus, in embodiments, a mifepristone doseadministered to a subject receiving concomitant administration ofmifepristone and ketoconazole may be reduced in compensation for such asmall increase in mifepristone plasma levels. In addition, as disclosedin Table 9 below, concomitant administration of mifepristone anditraconazole led to about 20% increase in mifepristone C_(max) and about10% increase in mifepristone AUC. Thus, in embodiments, a mifepristonedose administered to a subject receiving concomitant administration ofmifepristone and itraconazole may be reduced in compensation for such asmall increase in mifepristone plasma levels.

In embodiments in which a subject has been receiving a GRM such as,e.g., mifepristone, and concomitant administration of the GRM and aCYP3A inhibitor such as, e.g., ketoconazole or itraconazole, isindicated, the reduced dose of GRM may be reduced by about, e.g., 20% toabout 22%, of the original dose of GRM. In embodiments in which asubject has been receiving a GRM, and concomitant administration of theGRM and a CYP3A inhibitor such as, e.g., ketoconazole or itraconazole,is indicated, the reduced dose of GRM may be reduced by about 23% of theoriginal dose of GRM. In embodiments in which a subject has beenreceiving a GRM, and concomitant administration of the GRM and a CYP3Ainhibitor such as, e.g., ketoconazole or itraconazole, is indicated, thereduced dose of GRM may be reduced by about 28% of the original dose ofGRM. In embodiments in which a subject has been receiving a GRM, andconcomitant administration of the GRM and a CYP3A inhibitor such as,e.g., ketoconazole or itraconazole, is indicated, the reduced dose ofGRM may be reduced by about 29% of the original dose of GRM. Inembodiments, the reduced dose of GRM is a dose of GRM that is at leastabout 90% of the original dose of GRM; and may be a dose of GRM that isat least about 85%, or about 80%, or about 78%, or about 77%, or about75%, or about 72%, or about 71%, or about 67%, or about 62%, or about60%, or about 50%, or about 34%, or about 25% of the original dose ofGRM.

Applicant further discloses herein that, since mifepristone providesadded therapeutic benefit synergistic with steroidogenesis inhibitorssuch as, e.g., ketoconazole, levoketoconazole, metyrapone, etomidate,mitotane, osilodrostat (LCI699), concomitant administration ofmifepristone and such a steroidogenesis inhibitor makes it possible toreduce the dose of the steroidogenesis inhibitor while maintainingmifepristone levels effective for therapy for a patient. Such areduction in, e.g., ketoconazole dose provides the benefit of reducingthe risk of toxic side-effects associated with all ketoconazoletreatments. Thus, concomitant administration of a steroidogenesisinhibitor such as, e.g., ketoconazole or others, with mifepristone, byallowing reduced steroidogenesis inhibitor dose, provides improved,synergistic therapeutic benefits. In embodiments, such steroidogenesisinhibitor dose reduction may be used to wean the patient offsteroidogenesis inhibitor, leading to lower and lower steroidogenesisinhibitor doses, thereby reducing the risk of steroidogenesis inhibitortoxicity. In embodiments in which the steroidogenesis inhibitor isketoconazole, such ketoconazole dose reduction may be used to wean thepatient off ketoconazole, leading to lower and lower ketoconazole doses,with concomitant upward adjustment of mifepristone dosage as needed,ultimately leading to treatment with mifepristone alone and cessation ofketoconazole treatment (lessening the risk of liver damage and othertoxicities). Embodiments in which concomitant administration ofketoconazole and mifepristone may lead to ketoconazole dose reduction(as compared to the ketoconazole dose in the absence of mifepristone)include, e.g., Cushing's syndrome and hormone-sensitive cancers such asbreast, ovarian, and prostate cancer, and other disorders susceptible oftreatment by mifepristone.

In embodiments, concomitant administration of a steroidogenesisinhibitor, such as, e.g., ketoconazole, and mifepristone allows foradministration of an effective dose of the steroidogenesis inhibitorthat is a reduced dose of steroidogenesis inhibitor as compared to thesteroidogenesis inhibitor dose administered in the absence ofmifepristone. For example, Applicant discloses herein that concomitantadministration of mifepristone and ketoconazole makes it possible toreduce the dose of ketoconazole while maintaining effective therapy forthe patient. Such a reduction in ketoconazole dose provides the benefitof reducing the amount of ketoconazole administered to the subject.Embodiments in which a subject is concomitantly administeredketoconazole and mifepristone allow for ketoconazole dose reduction (ascompared to the ketoconazole dose in the absence of mifepristone)include, e.g., Cushing's syndrome and hormone-sensitive cancers such asbreast, ovarian, and prostate cancer, and other disorders susceptible oftreatment by ketoconazole and other steroidogenesis inhibitors.

In embodiments, the reduced dose of steroidogenesis inhibitor such as,e.g., ketoconazole, administered to a subject also concomitantlyreceiving mifepristone is a dose of steroidogenesis inhibitor that is atleast about 5% less than the original dose of steroidogenesis inhibitor,where the original dose of steroidogenesis inhibitor is the dose thesubject had been, or would have been, administered in the absence ofmifepristone co-administration. In embodiments, the reduced dose ofsteroidogenesis inhibitor is a dose of steroidogenesis inhibitor that isat least about 10% less than the original dose of steroidogenesisinhibitor; and may be a dose of steroidogenesis inhibitor that is atleast about 15%, or about 20%, or about 25%, or about 33%, or about 50%,or about 66%, or about 75% less than the original dose ofsteroidogenesis inhibitor.

Applicant discloses herein the use of a glucocorticoid receptormodulator (GRM) for treating Cushing's syndrome in a patient, whereinthe GRM is for once-daily administration, comprising reducing theonce-daily dose of said GRM from an original once-daily (OD) dose to anadjusted OD dose less than said original OD dose when the patient isreceiving concomitant administration of a CYP3A inhibitor. Inembodiments in which a once-daily dose of a GRM is used, and in whichconcomitant administration of GRM and a CYP3A inhibitor is indicated,the reduced dose of the GRM may be about at least about 15%, or about20%, or about 22%, or about 23%, or about 25%, or about 28%, or about29%, or about 33%, or about 38%, or about 40%, or about 50%, or about66%, or about 75% less than the original dose of the GRM. In embodimentsin which the once-daily dose of said GRM is about 1200 mg GRM per day,and concomitant administration of GRM and a CYP3A inhibitor isindicated, the reduced dose of GRM may be about 900 mg GRM per day; maybe greater than 800 mg GRM per day; may be about 600 mg GRM per day; ormay be about 300 mg GRM per day.

In embodiments, Applicant discloses herein the use of a glucocorticoidreceptor modulator (GRM) for treating Cushing's syndrome in a patient,wherein the GRM is for once-daily administration, comprising reducingthe once-daily dose of said GRM from an original once-daily (OD) dose toan adjusted OD dose that is at least about 25% less than said originalOD dose when the patient is receiving concomitant administration of aCYP3A inhibitor. In embodiments of such uses, said original once-daily(OD) dose is selected from greater than 800 mg/day, 900 mg per day and1200 mg per day of said GRM, and said adjusted OD dose is selected fromgreater than 800 mg/day and 600 mg per day of said GRM. In embodimentsof such uses, said original once-daily (OD) dose is 600 milligrams (mg)per day of said GRM, and said adjusted OD dose is 300 mg per day of saidGRM, further comprising titrating the adjusted OD dose to 600 mg per dayof said GRM. In embodiments of such uses, said GRM is mifepristone andsaid CYP3A inhibitor is a strong CYP3A inhibitor. In embodiments of suchuses, said CYP3A inhibitor is ketoconazole or itraconazole.

Applicant also discloses herein the use of a glucocorticoid receptormodulator (GRM) for treating symptoms associated with elevated cortisollevels in a patient, wherein the GRM is for once-daily administration,comprising reducing the once-daily (OD) dose of said GRM from anoriginal OD dose to an adjusted dose that is at least about 25% lessthan said original OD dose when the patient is receiving concomitantadministration of a CYP3A inhibitor. In embodiments of such uses, saidoriginal once-daily (OD) dose is selected from greater than 800 mg/day,900 mg per day and 1200 mg per day of said GRM, and said adjusted ODdose of GRM is 600 mg per day of said GRM. In embodiments of such uses,said original once-daily (OD) dose is 600 milligrams (mg) per day ofsaid GRM, and said adjusted OD dose is 300 mg per day of said GRM,further comprising titrating the adjusted OD dose to 600 mg per day ofsaid GRM. In embodiments of such uses, said GRM is mifepristone and saidCYP3A inhibitor is a strong CYP3A inhibitor. In embodiments of suchuses, said CYP3A inhibitor is ketoconazole or itraconazole.

Applicant further discloses herein the use of a GRM for controllinghyperglycemia secondary to hypercortisolism in a patient, wherein theGRM is for once-daily administration, comprising reducing the once-daily(OD) dose of said GRM from an original OD dose to an adjusted OD dosethat is at least about 25% less than said original OD dose when thepatient is receiving concomitant administration of a CYP3A inhibitor. Inembodiments of such uses, said original once-daily (OD) dose is 1200milligrams (mg) per day of said GRM, and said adjusted OD dose of GRM is900 mg per day of said GRM. In embodiments of such uses, said originalonce-daily (OD) dose is selected from greater than 800 mg/day, 900 mgper day and 1200 mg per day of said GRM, and said adjusted OD dose ofGRM is selected from greater than 800 mg/day and 600 mg per day of saidGRM. In embodiments of such uses, said once-daily dose of GRM istitrated up to greater than 800 mg/day, e.g., to 900 mg per day. Inembodiments of such uses, said original once-daily (OD) dose is 600milligrams (mg) per day of said GRM, and said adjusted OD dose is 300 mgper day of said GRM, further comprising titrating the adjusted OD doseto 600 mg per day of said GRM or to greater than 800 mg/day of said GRM.In embodiments of such uses, said GRM is mifepristone and said CYP3Ainhibitor is a strong CYP3A inhibitor. In embodiments of such uses, saidGRM is mifepristone and said CYP3A inhibitor is a strong CYP3Ainhibitor. In embodiments of such uses, said CYP3A inhibitor isketoconazole or itraconazole.

Applicant yet further discloses herein the use of a GRM for controllinghyperglycemia secondary to hypercortisolism in a patient with endogenousCushing's syndrome, wherein the GRM is for once-daily administration,comprising administering a once-daily dose of 600 milligrams (mg) GRM,such as, e.g., mifepristone, when the patient is receiving concomitantadministration of a CYP3A inhibitor. In embodiments of such uses, theCYP3A inhibitor is ketoconazole or itraconazole. In embodiments of suchuses, said once-daily dose of GRM is titrated up to greater than 800mg/day, e.g., to 900 mg per day following administration of a dose ordoses of 600 mg once per day. In embodiments of such uses, saidonce-daily dose of GRM is titrated up to 600 mg per day from 300 mg perday.

Applicant even further discloses herein the use of a GRM for controllinghyperglycemia secondary to hypercortisolism in a patient with endogenousCushing's syndrome, wherein the GRM is for once-daily administration,comprising administering a once-daily dose of greater than 800 mgmifepristone, e.g., 900 mg mifepristone when the patient is receivingconcomitant administration of a CYP3A inhibitor. In embodiments of suchuses, the CYP3A inhibitor is ketoconazole or itraconazole. Inembodiments of such uses, said once-daily dose of mifepristone istitrated up to greater than 800 mg/day, e.g., to 900 mg per day from 300mg per day.

Applicant provides definitions of some terms used in the presentdisclosure.

Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

“Patient”, “patient in need”, “subject”, “subject in need” and the likerefer to a person having, or suspected of having, a disease or conditionwhich may be treated by administration of a therapeutic drug.

As used herein, the term “Cushing's syndrome” refers to an array ofsymptoms caused by excess cortisol. Cushing's syndrome includesendogenous Cushing's syndrome and ectopic Cushing's syndrome. Suchsymptoms include, for example, elevated blood pressure, elevated bloodglucose, increased weight (typically in the mid-section, and in the facecausing a characteristic “moon-face”), immune suppression, thin skin,acne, depression, hirsutism, and other symptoms.

As used herein, “Cushing's Disease” refers to pituitary-dependentCushing's syndrome, e.g., excess cortisol caused by pituitaryabnormality (typically a pituitary tumor). Cushing's Disease is thus adisease that is a particular type of Cushing's syndrome. The termCushing's syndrome thus includes reference to Cushing's Disease.

As used herein, a “patient suffering from Cushing's syndrome” refers toany patient suffering from Cushing's syndrome, including endogenousCushing's syndrome; Cushing's Disease; or a condition associated withCushing's syndrome. A condition associated with Cushing's syndrome maybe, without limitation, a condition associated with endogenous Cushing'ssyndrome; hyperglycemia secondary to hypercortisolism; a condition ofhypercortisolism in an endogenous Cushing's syndrome patient, saidpatient having type 2 diabetes mellitus or glucose intolerance; acondition of hyperglycemia secondary to hypercortisolism in anendogenous Cushing's syndrome patient, said patient having type 2diabetes mellitus or glucose intolerance and having failed surgery;hyperglycemia secondary to hypercortisolism in an endogenous Cushing'ssyndrome patient, said patient having type 2 diabetes mellitus orglucose intolerance and having failed surgery or who is not a candidatefor surgery; and other conditions associated with Cushing's syndrome.

“Treat”, “treating” and “treatment” refer to any indicia of success inthe treatment or amelioration of a pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the pathology or condition moretolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating; orimproving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination;histopathological examination (e.g., analysis of biopsied tissue);laboratory analysis of urine, saliva, tissue samples, serum, plasma, orblood; or imaging.

As used herein, “treating a patient who is suffering from Cushing'ssyndrome”, or treating a subject who is suffering from Cushing'ssyndrome”, or similar phrases refer to, without limitation, treating apatient suffering from Cushing's syndrome, including endogenousCushing's syndrome; treating a patient suffering from Cushing's Disease;or treating a patient suffering from a condition associated withCushing's syndrome. A condition associated with Cushing's syndrome isdiscussed above. For example, treating a patient who is suffering fromCushing's syndrome may include administering mifepristone or other GRAto control hyperglycemia secondary to hypercortisolism in adult patientswith endogenous Cushing's syndrome who have type 2 diabetes mellitus orglucose intolerance and have failed surgery or are not candidates forsurgery.

As used herein, the term “administration” refers to the delivery of adrug or other therapeutic into the body of a patient in need oftreatment by the drug or therapeutic, effective to achieve a therapeuticeffect. Administration may be by any suitable route of administration,including, for example, oral administration; intravenous administration;subcutaneous administration; parenteral administration; intra-arterialadministration; nasal administration; topical administration; and otherroutes of administration.

As used herein, the terms “percent”, “%” and “weight percent” whenapplied to a dosage administered to a subject, all refer to a percentagetaken by comparing the weight of a first dose to that of a second dose,and multiplying the resulting decimal fraction by 100. Thus, forexample, where an original mifepristone dose is 1200 milligrams (mg), adose that is reduced by 50% is a dose of 600 mg mifepristone; and wherean original mifepristone dose is 600 milligrams (mg), a dose that isreduced by 50% is a dose of 300 mg mifepristone; and so forth.

As used herein, the phrases “less than x by at least”, “less than x byat least about”, and the like refer to amounts equal to and less thanthe x, where x is a number. For example, the phrase “less than theoriginal dosage by at least 25%” refers to dosage amounts that include25% less than the original dosage as well as other percentages (e.g.,26%, 28%, etc.) less than the original dosage amount.

As used herein, the terms “effective amount,” “amounts effective,”therapeutic amount”, and “therapeutically effective amount” refer to anamount or amounts of one or more pharmacological agents effective totreat, eliminate, or mitigate at least one symptom of the disease beingtreated. In some cases, “effective amount,” “amounts effective,”“therapeutic amount”, and “therapeutically effective amount” can referto an amount of a functional agent or of a pharmaceutical compositionuseful for exhibiting a detectable therapeutic or inhibitory effect.

As used herein, the term “simultaneously or sequentially administering”refers to administration of two compounds, such as a GRA and a CYP3Ainhibitor, such that the two compounds are in the body at the same timein therapeutically effective amounts.

As used herein, “concomitant” means at the same, or nearly the same,time, and “concomitantly” refers to actions performed at the same, ornearly the same, time. As used herein, he terms “concurrent” and“concomitant” are equivalent and may be used interchangeably. Theadverbs “concurrently” and “concomitantly” are equivalent and may beused interchangeably.

As used herein, the term “concomitant administration” of two or moredrugs means administering two or more drugs at the same, or nearly thesame, time. Concomitant administration of two or more drugs providestherapeutically effective amounts of the two or more drugs in the systemof the subject at the same time. Concomitant administration includesadministration of a GRA to a patient who has previously beenadministered a drug, such as a CYP3A inhibitor or a steroidogenesisinhibitor, and therapeutically effective levels of the CYP3A inhibitoror steroidogenesis inhibitor remain in the patient when the patient isadministered the GRA (e.g., when the patient is administeredmifepristone), and includes administration of a CYP3A inhibitor or asteroidogenesis inhibitor to a patient who has previously beenadministered a drug, such as a GRA, and therapeutically effective levelsof the GRA remain in the patient when the patient is administered theCYP3A inhibitor or steroidogenesis inhibitor.

As used herein, “concomitantly administering drugs” means that two ormore drugs are administered to a subject at the same, or nearly thesame, time. Drugs that are concomitantly administered will each bepresent in therapeutically effective amounts in the system of thesubject at the same time. Nearly the same time means that only a shortamount of time separates two events, such as administration of a firstdrug and the administration of a second drug.

Events or actions that are “simultaneous” or that occur or are performed“simultaneously” are events that occur or are performed at the sametime.

As used herein, “at the same time” means that two events occur or areperformed within about five minutes of each other.

As used herein, “nearly the same time” means that two events occur orare performed within about a short time of each other.

As used herein, a “short time”, a “short amount of time”, a “shortperiod of time”, and the like mean a time that is less than about twohours, or less than about one hour, or less than about 45 minutes, orless than about 30 minutes, or less than about 20 minutes, or less thanabout 10 minutes, or less than about 7 minutes.

As used herein, the term “clinical effect” means changes in symptoms orsigns characteristic of, or indicative of, a clinical condition ordisorder. For example, where a subject is treated for Cushing'ssyndrome, including Cushing's Disease, a clinical effect may be a changein any one or more of blood pressure, blood glucose, other pre-diabeticsymptom, weight, mid-section perimeter, facial characteristics (e.g.,change in “moon-face” appearance), immune function, skin thickness,acne, depression or other mood symptom, hirsutism, and other symptoms.

As used herein, “monitoring for clinical response”, e.g., monitoring apatient for clinical response to a GRA such as mifepristone, may includemonitoring the patient (e.g., to identify or determine if there arechanges in) for glucose control, anti-diabetic medication requirement,insulin level, psychiatric symptoms, cushingoid appearance, acne,hirsutism, and monitoring the body weight of the patient (e.g., toidentify or determine if there are changes in any one or more of thesesymptoms and characteristics). Monitoring for clinical response may alsoinclude monitoring a patient for adverse events, for side-effects of anydrug (including a GRA, a CYP3A inhibitor, a steroidogenesis inhibitor,and combinations of these). Thus, monitoring for clinical response mayinclude monitoring for clinical effect of a drug such as a GRM,including clinical efficacy of the GRM; for clinical effect of asteroidogenesis inhibitor or CYP3A inhibitor; for possible adversereaction to a steroidogenesis inhibitor or CYP3A inhibitor; for possibleadverse reaction to the use of a steroidogenesis inhibitor or CYP3Ainhibitor in combination with the GRM; for possible side-effects of asteroidogenesis inhibitor or CYP3A inhibitor, or their use incombination with the GRM; or combinations thereof.

As used herein, the term “AUC” means the area under the plasmaconcentration-time curve, and serves as a measure of the plasma levelsof a drug in a subject to whom the drug has been administered.

As used herein, the term “C_(max)” means the maximum observed plasmaconcentration of a drug in a subject to whom the drug has beenadministered.

As used herein, the term “binding” refers to persistent contact, oradherence (however brief or intermittent), between two compounds.

As used herein, the terms “affinity”, “binding affinity”, and relatedterms refer to the strength and specificity of binding, such as bindingbetween a ligand and its receptor. “Higher affinity” is used withreference to comparative binding between two ligands to a receptor,where the ligand which binds with higher affinity binds at a lowerconcentration than does the “lower affinity” ligand. For example, in acompetitive binding experiment, a high affinity ligand will compete witha reference ligand for binding to a receptor at a lower concentrationthan will the low affinity ligand compete for binding at the receptor.

The term “specific binding” refers to binding that is more selective,and typically stronger, than mere non-specific adhesion betweencompounds. Specific binding may be exemplified by the binding whichoccurs between a ligand and its receptor.

Description of compounds useful in the methods disclosed herein, andsuitable for the pharmaceutical compositions disclosed herein aredescribed in accordance with principles of chemical bonding known tothose skilled in the art. Accordingly, where a group may be substitutedby one or more of a number of substituents, such substitutions areselected so as to comply with principles of chemical bonding and to givecompounds which are not inherently unstable and/or would be known to oneof ordinary skill in the art as likely to be unstable under ambientconditions, such as aqueous, neutral, or physiological conditions.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, etc.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆. For example, haloalkyl includes trifluoromethyl, fluoromethyl,etc. In some instances, the term “perfluoro” can be used to define acompound or radical where all the hydrogens are replaced with fluorine.For example, perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O and S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8,6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, having a methylene linking group. Some arylgroups have from 6 to 12 ring members, such as phenyl, naphthyl orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O or S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)— and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline,benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples of pharmaceuticallyacceptable salts are mineral acid (hydrochloric acid, hydrobromic acid,phosphoric acid, and the like) salts, organic acid (acetic acid,propionic acid, glutamic acid, citric acid and the like) salts,quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.It is understood that the pharmaceutically acceptable salts arenon-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

As used herein, the term “ketoconazole” refers to the molecule havingthe chemical name“1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)”;it is sold for clinical use under the name “NIZORAL®”, and may also bereferred to by the abbreviation “keto”.

As used herein, the terms “steroid” and “steroids”, and the phrase“steroidal backbone” in the context of glucocorticoid receptorantagonists containing such refers to glucocorticoid receptorantagonists that contain modifications of the basic structure ofcortisol, an endogenous steroidal glucocorticoid receptor ligand. Thebasic structure of a steroidal backbone is provided as Formula I:

The two most commonly known classes of structural modifications of thecortisol steroid backbone to create glucocorticoid antagonists includemodifications of the 11-β hydroxy group and modification of the 17-βside chain (See, e. g., Lefebvre (1989) J. Steroid Biochem. 33:557-563).

As used herein, the terms “progesterone receptor” and “PR” refer to anaturally occurring receptor which binds progesterone.

The term “aldosterone” refers to the naturally occurringmineralocorticoid hormone having the structure:

A mineralocorticoid receptor (MR), also known as a type I glucocorticoidreceptor (GR I), is activated by aldosterone in humans.

The term “cortisol” refers to the naturally occurring glucocorticoidhormone (also known as hydrocortisone) having the structure:

As used herein, the term glucocorticoid receptor (GR) refers to areceptor that binds a glucocorticoid, such as cortisol, dexamethasone,or other molecules. A glucocorticoid receptor, also known as acorticosteroid receptor or as a type II glucocorticoid receptor (GR II),and in humans, as a cortisol receptor, is activated by cortisol inhumans (or, e.g., by corticosterone (“cortisone”) in some other animals,such as rats and mice). The human cortisol receptor (GR II receptor,Genbank: P04150) specifically binds to cortisol and/or cortisol analogs(e.g. dexamethasone). The term includes isoforms of GR II, recombinantGRII, and mutated GRII.

As used herein, the term glucocorticoid receptor modulator (GRM) refersto an agent that affects the action of a glucocorticoid receptor (GR).Such modulation may include activation (agonist action), partialactivation (partial agonist action), inhibition (reduction in activationof the receptor under conditions where it would otherwise be activated,such as in the presence of cortisol), and blockade (complete or nearcomplete suppression of activation of the receptor under conditionswhere it would otherwise be activated, such as in the presence ofcortisol). GRMs may affect the activity of a GR by increasing or bydecreasing the activity of the GR. GRMs include steroids, and, inembodiments, include pyrimidinediones; azadecalins; fused-ringazadecalins; heteroaryl-ketone fused-ring azadecalins; and othercompounds.

As used herein, the terms “glucocorticoid agonist”, “glucocorticoidreceptor agonist”, “glucocorticoid receptor type II agonist”, and “GRIIagonist” refer to a compound or agent which may bind to and activate acortisol receptor. Such agents include, for example, cortisol,dexamethosone, prednisone, and other compounds and agents which bind toand activate a GRII.

As used herein, the terms “glucocorticoid antagonist”, “glucocorticoidreceptor antagonist”, “glucocorticoid antagonist”, “glucocorticoidreceptor type II antagonist”, “GRII antagonist”, and “GRA” refer toagents that inhibit the action of a cortisol receptor; such inhibitionmay include interfering with the binding of a glucocorticoid agonistsuch as cortisol, dexamethosone, or other compound or agent which maybind to and activate a cortisol receptor. A GRA is a glucocorticoidreceptor modulator. Inhibition constants (K_(i)) for GRAs against thehuman cortisol receptor may be between about 0.0001 nM and about 1,000nM; preferably may be between about 0.0005 nM and about 10 nM, and mostpreferably between about 0.001 nM and about 1 nM.

The term “glucocorticoid receptor antagonist” refers to any compositionor compound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “specificglucocorticoid receptor antagonist” refers to any composition orcompound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” we intend the drug topreferentially bind to the GR rather than another nuclear receptors,such as mineralocorticoid receptor (MR) or progesterone receptor (PR).

By “specific,” the drug preferentially binds to the GR rather than othernuclear receptors, such as mineralocorticoid receptor (MR), androgenreceptor (AR), or progesterone receptor (PR). It is preferred that thespecific glucocorticoid receptor antagonist bind GR with an affinitythat is 10× greater ( 1/10^(th) the K_(d) value) than its affinity tothe MR, AR, or PR. In a more preferred embodiment, the specificglucocorticoid receptor antagonist binds GR with an affinity that is100× greater ( 1/100^(th) the K_(d) value) than its affinity to the MR,AR, or PR.

In embodiments, a glucocorticoid receptor modulator (GRM) is aglucocorticoid receptor antagonist (GRA). In embodiments, the GRA is anantagonist of a glucocorticoid type II (GRII) receptor. In embodiments,the GRA binds preferentially to a GRII receptor as compared to itsbinding to a glucocorticoid type I (GRI) receptor. In embodiments, theGRA reduces the activation of a GRII receptor. In embodiments, the GRAreduces the activity of a GRII receptor. In embodiments, the GRA maybind to a progesterone receptor (PR), and may bind to a glucocorticoidreceptor with higher affinity than it binds to PR. In embodiments, theGRA is mifepristone. In embodiments, the GRA is a selective inhibitor ofthe glucocorticoid receptor. In embodiments, the GRA may only poorlybind to PR, or may not measurably bind to PR.

As used herein, a “steroidal glucocorticoid receptor antagonist” means amolecule including a steroid backbone structure which antagonizes thebinding of cortisol, corticosterone, or dexamethasone to aglucocorticoid receptor, or which reduces or blocks the activation of aglucocorticoid receptor by cortisol, corticosterone, or dexamethasone.Examples of steroidal glucocorticoid receptor antagonists includemifepristone, monodemethylated mifepristone, didemethylatedmifepristone, 17-α-[3′-hydroxy-propynyl]mifepristone, ulipristal(CDB-2914), CDB-3877, CDB-3963, CDB-3236, CDB-4183, cortexolone,dexamethasone-oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone,cortisol-21-mesylate; dexamethasone-21-mesylate,11(-(4-dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,9-estradien-3one,and 17(-hydroxy-17(-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one.

Mifepristone is a glucocorticoid receptor modulator (GRM), and inparticular, is a glucocorticoid receptor antagonist (GRA), which bindsto GRII (and which also binds to a progesterone receptor). As usedherein, the term “mifepristone” refers to11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one),also referred to as RU486, or as RU38.486, or as17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one).Mifepristone binds to the glucocorticoid receptor (GR), typically withhigh affinity, and inhibits the biological effects initiated/mediated bythe binding of any cortisol or cortisol analogue to a GR receptor.Salts, hydrates and prodrugs of mifepristone are all included in theterm “mifepristone” as used herein. Thus, used herein, “mifepristone”refers to the molecule that has the following structure:

and to salts, hydrates and prodrugs thereof, and pharmaceuticalcompositions thereof. Mifepristone is also sometimes abbreviated as“mife” and “MIFE”.

Metabolites of mifepristone include RU42633 (desmethylmifepristone:(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-[4-(methylamino)phenyl]-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one);RU42698 (22-hydroxy mifepristone:(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxyprop-1-ynyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one);and RU42848 (didesmethylmifepristone:(8S,11R,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one),among others.

In some embodiments, the GRA comprises a steroidal backbone with atleast one phenyl-containing moiety in the 11-β position of the steroidalbackbone. In some cases, the phenyl-containing moiety in the 11-βposition of the steroidal backbone is a dimethylaminophenyl moiety. Insome cases, the GRA is mifepristone. In some embodiments, the GRA isselected from the group consisting of11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. In someembodiments, the GRA is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

As used herein, the phrase “non-steroidal backbone” in the context ofglucocorticoid receptor antagonists containing such refers toglucocorticoid receptor antagonists that do not share structuralhomology to, or are not modifications of, cortisol. Such compoundsinclude, for example, small molecules, synthetic mimetics and analogs ofproteins, including partially peptidic, pseudopeptidic and non-peptidicmolecular entities.

In some embodiments, the GRA is a non-steroidal compound. Inembodiments, non-steroidal GRA compounds include compounds having acyclohexyl-pyrimidine backbone; non-steroidal GRA compounds having afused azadecalin backbone; non-steroidal GRA compounds having aheteroaryl ketone fused azadecalin backbone; and non-steroidal GRAcompounds having an octahydro fused azadecalin backbone. Exemplaryglucocorticoid receptor antagonists having a cyclohexyl-pyrimidinebackbone include those described in U.S. Pat. No. 8,685,973. Exemplaryglucocorticoid receptor antagonists having a fused azadecalin backboneinclude those described in U.S. Pat. Nos. 7,928,237; and 8,461,172.Exemplary glucocorticoid receptor antagonists having a heteroaryl ketonefused azadecalin backbone include those described in U.S. Pat. No.8,859,774. Exemplary glucocorticoid receptor antagonists having anoctohydro fused azadecalin backbone include those described in U.S.Patent Application Publication 20150148341.

In some cases, the GRA having a non-steroidal backbone is a cyclohexylpyrimidine. In some cases, wherein the cyclohexyl pyrimidine has thefollowing formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b), NR^(1b)R^(1c) C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c)cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.

In some cases, the GRA having a non-steroidal backbone is a fusedazadecalin. In some cases, the fused azadecalin is a compound having thefollowing formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D) and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.

In some cases, the GRA having a non-steroidal backbone is a heteroarylketone fused azadecalin or an octahydro fused azadecalin. In some cases,the heteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy,CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b),SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2c) groups; alternatively, two R² groups linkedto the same carbon are combined to form an oxo group (═O);alternatively, two R² groups are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2d) groups; R^(2a) and R^(2b) are each independently selected fromthe group consisting of hydrogen and C₁₋₆ alkyl; each R^(2c) isindependently selected from the group consisting of hydrogen, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, CN, and NR^(2a)R^(2b); eachR^(2d) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl, or two R^(2d) groups attached to the same ring atom arecombined to form (═O); R³ is selected from the group consisting ofphenyl and pyridyl, each optionally substituted with 1-4 R^(3a) groups;each R^(3a) is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₆ haloalkyl; and subscript n is an integerfrom 0 to 3; or salts and isomers thereof.

In some cases, the octahydro fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.

Further examples of non-steroidal glucocorticoid receptor antagonistsinclude, for example N-(2-[4,4′,441-trichlorotrityl]oxyethyl)morpholine;1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazinedimaleate; N—([4,4′,4″ ]-trichlorotrityl)imidazole;9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone;1-(2-chlorotrityl)-3,5-dimethylpyrazole;4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol;5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol;N-(2-chlorotrityl)-L-prolinol acetate;1-(2-chlorotrityl)-1,2,4-triazole;1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol;4a(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 394531”),4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP-409069”), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-1pyrrolidinyl)cyclohexyl]benzeneacetamide, bremazocine, andethylketocyclazocine.

As used herein, the term “hormone-sensitive cancer” refers to any cancerwhich may be affected by a hormone; hormones typically increaseproliferation of hormone-sensitive cancers. Hormone sensitive cancersinclude, e.g., prostate cancer and other androgen-sensitive cancers;breast cancer, ovarian cancer and other estrogen-sensitive orprogesterone-sensitive cancers.

As used herein, the term “chemotherapy” refers to medical treatmentstypically used to treat cancer. Chemotherapy treatments include the useof agents which are toxic to cancerous tissues and cells, or which actto slow or reduce the growth or spread of cancerous tissues and cells.Chemotherapy agents include antineoplastic agents and may be derivedfrom natural compounds (e.g., taxols); may be, may mimic, or may reduceor block the actions of naturally occurring hormones, growth factors, orimmunologically active molecules; may be synthetic small molecules; maybe antibodies or antibody conjugates; and may be other agents. Exemplarychemotherapy agents include, but are not limited to, taxanes, taxol,docetaxel, paclitaxel, actinomycin, anthracyclines, doxorubicin,daunorubicin, valrubicin, bleomycin, cisplatin, trastuzumab(HERCEPTIN®), trastuzumab emtasine (KADCYLA®), imatinib (GLEEVEC®),eribulin (HALAVEN®), among others known in the art.

As used herein, a phrase of the form “the reduced dose of Z is a dosethat is at least about X % less than the original dose” (where “Z”represents a pharmaceutical compound or pharmaceutical composition, and“X” represents a numerical value) is used to indicate that the reduceddose is an amount of Z calculated by 1) multiplying the amount of Z inthe original dose by X % to obtain a multiplicative product, and 2)subtracting that product from the original dose. Thus, for example,where the original dose is 600 mg, and X % is 50%, the multiplicativeproduct of 600 mg and 50% is 300 mg, and the reduced dose is 300 mg;and, for example, where the original dose is 900 mg, and X % is 66%, themultiplicative product of 900 mg and 66% is about 600 mg (594 mg), andthe reduced dose is about 300 mg (306 mg).

As used herein, the terms “pharmaceutical composition” and “formulation”refer to compositions suitable for administration to a patient fortreatment of a medical condition or for amelioration of symptoms of amedical condition. A pharmaceutical composition as disclosed hereinincludes an active ingredient (e.g., a GRA, such as, e.g., mifepristone;or a combination of a GRA and a SI, where the SI may be, e.g.,ketoconazole) and a pharmaceutically acceptable excipient. Inembodiments, a pharmaceutical composition includes one or more activeingredients and one or more pharmaceutically acceptable excipients.

As used herein, the terms “pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids theadministration of an active agent to and absorption by a subject and canbe included in the compositions of the present invention without causinga significant adverse toxicological effect on the patient. Non-limitingexamples of pharmaceutically acceptable excipients include water, NaCl,normal saline solutions, lactated Ringer's, normal sucrose, normalglucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors and colors, and the like. One of skill in the artwill recognize that other pharmaceutical excipients are useful in thepresent invention.

As used herein, the terms “sustained release,” “slow release,” “longacting,” “prolonged release,” and the like refer to a pharmaceuticalcomposition or formulation containing at least one active ingredient(e.g., GRA, SI, or combination thereof) formulated to maintain atherapeutic concentration of active ingredient(s) in a patient for alonger period of time in comparison to formulations that are notdesigned for such sustained release. In some cases, the sustainedrelease formulation maintains therapeutic concentration of one or moreactive ingredient(s) for, or for at least, one week, two weeks, threeweeks, four weeks, five weeks, or six weeks. In some cases, thesustained release formulation is administered to a patient every one,two, three, four, five, or six weeks.

As used herein, a “steroidogenesis inhibitor” is a compound whichreduces or blocks the synthesis of steroid molecules when administeredto an animal, or subject, which normally produces steroids.Steroidogenesis inhibitors include, for example, ketoconazole,levoketoconazole, metyrapone, etomidate, mitotane, osilodrostat(LCI699), and other drugs. A steroidogenesis inhibitor may act by one ormore of several mechanisms, including, e.g., blocking synthesis ofsteroid molecules (e.g., ketoconazole, metyrapone).

As used herein, the term “CYP enzyme” refers to a cytochrome P450enzyme. Cytochrome P450 enzymes are important in many metabolic andcatabolic reactions in humans and other animals, and play importantroles in drug metabolism and action. Drug-drug interactions in whichadministration of one drug affects the concentration, half-life,activity, or other effect of another drug may include effects on CYPenzymes by induction of CYP enzymes (increasing the amount or activityof one or more CYP enzymes); inhibition (reducing the activity of one ormore CYP enzymes); competition (competing for sites or occupying sites,e.g., as a substrate, of one or more CYP enzymes); or by other means.Particular CYP enzymes include, for example, CYP1A2, CYP2C9, CYP2C19,CYP2D6, and CYP3A enzymes.

As used herein, a “CYP3A inhibitor” is a compound which reduces orblocks the activity of the cytochrome CYP3A, or reduces or blocks theexpression of the gene-product of CYP3A genes (e.g., inhibitstranscription or translation of CYP3A genes). CYP3A inhibitors may betermed strong or moderate if their administration, along with a testdrug known to be metabolized by CYP3A enzymes (such as, e.g.,midazolam), raises the AUC (area under the concentration curve) of thetest drug by greater than five-fold (strong CYP3A inhibitors) or bybetween two-fold and five-fold (moderate CYP3A inhibitors). Inhibitorsof CYP3A include, for example, ketoconazole, itraconazole, fluconazole,cimetidine, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan,lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, andvoriconazole.

Strong CYP3A inhibitors include, for example, ketoconazole,itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,amprenavir and fosamprenavir, clarithromycin, conivaptan,lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, andvoriconazole.

Metyrapone (also known as METOPIRONE®) is2-methyl-1,2-bis-(3-pyridyl)-1-propanone. Metopirone is believed toreduce cortisol and corticosterone production by inhibiting the11-β-hydroxylation reaction in the adrenal cortex.

Etomidate (also known as AMIDATE®) isR-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate. Althoughprimarily used as a rapid-onset anesthetic, etomidate also lowers plasmacortisol levels. It is believed to reduce corticosteroid synthesis inthe adrenal cortex by inhibiting 11β-hydroxylase.

Ketoconazole(1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)is often used to treat fungal infections (e.g., (NIZORAL®) for thetreatment of fungal infections). In addition, ketoconazole is asteroidogenesis inhibitor and can reduce the production of steroidmolecules (such as, e.g., steroid hormones), typically by blocking themetabolism of cholesterol. Ketoconazole thus may be used to treatexcessive cortisol production (e.g., to treat Cushing's disease andCushing's syndrome), to reduce androgen production (e.g., in patientswith hormone-sensitive cancers such as prostate cancer), to reduceestrogen or progesterone production (e.g., in patients withhormone-sensitive cancers such as breast cancer), and other treatments.

However, ketoconazole and itraconazole often have serious deleteriouseffects on liver and other organs. Thus, it is desirable to minimize thedose of ketoconazole or itraconazole administered to a patient, andmethods for reducing the dose of ketoconazole or itraconazole aredesired.

Treatment Methods

Methods disclosed herein include methods of treating a diseasecharacterized by excess steroid levels, or by excess activity due tosteroids. Methods disclosed herein also include methods of treating adisease that may be treated by reducing or blocking the action ofsteroids, such as steroid hormones. In embodiments, the disease ischaracterized by excess cortisol levels, such as, e.g., Cushing'ssyndrome, and in particular, Cushing's Disease. (As noted above, bothCushing's syndrome and Cushing's Disease are characterized by excesscortisol; Cushing's Disease falls within the definition of Cushing'ssyndrome as a particular type or example of Cushing's syndrome; thus,all discussion and disclosure regarding Cushing's syndrome includesCushing's Disease.) Methods disclosed herein also include methods oftreating cancer and cancerous tumors, such as hormone-sensitive cancersincluding prostate cancer, comprising concomitant administration of aGRM and a steroidogenesis inhibitor such as ketoconazole to providethereby beneficial therapeutic effects. Methods, compositions, and kitsdisclosed herein are related to the methods compositions, and kits andcompositions disclosed in U.S. Provisional Patent Application Ser. No.62/465,772, filed Mar. 1, 2017, and U.S. Provisional Patent ApplicationSer. No. 62/466,867, filed Mar. 3, 2017, which applications are herebyincorporated by reference in their entireties.

For example, the present methods include concomitantly administering toa patient a CYP3A inhibitor and a glucocorticoid receptor modulator(GRM), such as a glucocorticoid receptor antagonist (GRA). Inembodiments, the CYP3A inhibitor is ketoconazole or itraconazole. Inembodiments, the CYP3A inhibitor is ketoconazole or itraconazole and theGRA is mifepristone. In embodiments, the patient is receiving a CYP3Ainhibitor (such as, e.g., ketoconazole or itraconazole) and isconcomitantly administered an amount of a GRM (such as, e.g.,mifepristone) effective to treat Cushing's syndrome, e.g., effective tocontrol hyperglycemia secondary to hypercortisolism in an adult patientsuffering from endogenous Cushing's syndrome. In embodiments, the adultpatient suffering from endogenous Cushing's syndrome has type 2 diabetesmellitis or glucose intolerance. In embodiments, the adult patientsuffering from endogenous Cushing's syndrome has failed surgery or isnot a candidate for surgery (e.g., referring to surgical treatment forCushing's syndrome). In embodiments, the adult patient suffering fromendogenous Cushing's syndrome has type 2 diabetes mellitis or glucoseintolerance and has failed surgery or is not a candidate for surgery(e.g., referring to surgical treatment for Cushing's syndrome).

In embodiments, the present methods include methods for treatingCushing's syndrome in a patient taking a GRM, comprising reducing thedaily dosage amount of the GRM from an original GRM dose to an adjustedGRM dose when the patient is receiving concomitant administration of aCYP3A inhibitor. In embodiments, the adjusted dose of GRM is at least20% less than the original dose. In embodiments, the adjusted dose ofGRM is at least 25% less than the original dose. In embodiments, theadjusted dose of GRM is at least 33% less than the original dose. Inembodiments, the adjusted dose of GRM is less than the original dose bya fraction of the original dose selected from 10%, 20%, 25%, 30%, 33%,33^(1/3)%, and 50%. In embodiments, the GRM is mifepristone, and theadjusted mifepristone dose is selected from 300 mg per day, 600 mg perday, and 900 mg per day. In embodiments, the CYP3A inhibitor isketoconazole or itraconazole. In embodiments, the CYP3A inhibitor isketoconazole and the GRM is mifepristone. In embodiments, the patient isreceiving a CYP3A inhibitor (such as, e.g., ketoconazole oritraconazole) and is concomitantly administered an amount of a GRM (suchas, e.g., mifepristone) effective to treat Cushing's syndrome, e.g.,effective to control hyperglycemia secondary to hypercortisolism in anadult patient suffering from endogenous Cushing's syndrome. Inembodiments, the adult patient suffering from endogenous Cushing'ssyndrome has type 2 diabetes mellitis or glucose intolerance. Inembodiments, the adult patient suffering from endogenous Cushing'ssyndrome has failed surgery or is not a candidate for surgery (e.g.,referring to surgical treatment for Cushing's syndrome). In embodiments,the adult patient suffering from endogenous Cushing's syndrome has type2 diabetes mellitis or glucose intolerance and has failed surgery or isnot a candidate for surgery (e.g., referring to surgical treatment forCushing's syndrome).

For example, the present disclosed methods include administering to apatient receiving ketoconazole or itraconazole an effective amount of aGRM, such as a GRA. In embodiments, the patient is receivingketoconazole. In embodiments, the patient is receiving ketoconazole andthe GRM is mifepristone. In embodiments, the patient is receivingketoconazole and is administered an amount of mifepristone effective toreduce the effect of a steroid such as cortisol in the patient. Inembodiments, the patient is receiving itraconazole. In embodiments, thepatient is receiving itraconazole and the GRM is mifepristone. Inembodiments, the patient is receiving itraconazole and is administeredan amount of mifepristone effective to reduce the effect of a steroidsuch as cortisol in the patient.

Thus, in embodiments, the methods disclosed herein include a method fortreating a patient who is receiving ketoconazole or itraconazoletreatment for excess steroid levels, said ketoconazole treatmentcomprising administering an original dose of ketoconazole oritraconazole to said patient, said method comprising: administering aGRM to the patient receiving ketoconazole or itraconazole, whereby thepatient receiving ketoconazole or itraconazole is administered a GRM fortreating excess steroid levels. In embodiments, the GRM is mifepristone.In embodiments, the disease is Cushing's syndrome. In embodiments, thedisease is Cushing's Disease.

Thus, in embodiments, the methods disclosed herein include a method fortreating a patient who is receiving ketoconazole treatment to reduce orblock the effects of steroids, said ketoconazole treatment comprisingadministering an original dose of ketoconazole or itraconazole to saidpatient, said method comprising: administering a GRM to the patientreceiving ketoconazole or itraconazole, whereby the patient receivingketoconazole or itraconazole is administered a GRM for treating theeffects of steroids in the patient. In embodiments, the GRM ismifepristone. In embodiments, the effects of steroids includehypercortisolemic effects, such as the effects of Cushing's syndrome. Inembodiments, the effects of steroids include hormonal effects, such aseffects on hormone-sensitive cancer.

Applicant further discloses a method for treating a Cushing's syndromepatient who is receiving ketoconzole or itraconazole treatment, saidketoconzole or itraconazole treatment comprising administering anoriginal dose of ketoconzole or itraconazole to said patient, saidmethod comprising: administering a GRM to the patient receivingketoconzole or itraconazole, wherein the amount of GRM administered is afirst dose of GRM, whereby the patient receiving ketoconzole oritraconazole is administered a GRM for treating Cushing's syndrome. Inembodiments, the GRM is mifepristone. In embodiments, the or Cushing'ssyndrome patient suffers from Cushing's Disease.

For example, the present disclosed methods include concomitantlyadministering to a patient in need thereof, a) an effective amount of aGRM, such as a GRA, and b) an effective amount of a CYP3A inhibitor,such as ketoconazole or itraconazole, or a steroidogenesis inhibitorsuch as ketoconazole, thereby reducing the effect, the amount, or both,of steroids such as cortisol in the patient. For example, a Cushing'ssyndrome patient may be in need of reducing their blood levels ofcortisol, or may be in need of reducing the effect of cortisol in thepatient. For example, a cancer patient may be in need of reducing theirblood levels of a steroid, such as an androgen, a progestogen, anestrogen, or other steroid.

Thus, in embodiments of the methods disclosed herein, a subjectcurrently receiving ketoconazole or itraconazole is administered a GRM.In embodiments of the methods disclosed herein, a subject currentlyreceiving ketoconazole or itraconazole as treatment for a conditioncharacterized by excess steroid levels, or as treatment of a conditionthat is treated by reducing steroid levels or by reducing steroideffects, is administered a GRM, whereby the subject is treated for thatcondition. In embodiments, the condition is characterized by excessivecortisol levels. In embodiments, the condition is Cushing's syndrome. Inembodiments, the condition is a cancer characterized by the deleteriousaction of steroid hormones on cells, such as cancer cells; the cancermay be hormone-sensitive cancer that may be treated by lowering thelevels of a steroid in the patient. In embodiments, the hormonesensitive cancer is prostate cancer, breast cancer, or ovarian cancer.

Accordingly, Applicant discloses herein a method for treating a patientin need of reduced steroid levels, the patient receiving an originaldose of ketoconazole or itraconazole, said method comprising:

administering a first dose of a glucocorticoid receptor modulator (GRM)to the patient, wherein said first GRM dose is administeredconcomitantly with said dose of ketoconazole or itraconazole, wherebythe patient is administered both an original dose of ketoconazole oritraconazole and a first dose of a GRM for reducing steroid levels inthe patient. In embodiments of such methods, wherein said first dose ofGRM comprises an amount of the GRM that is effective to aid in reducingsteroid levels in the patient without substantially increasing the levelof ketoconazole or itraconazole in the blood of the patient above thatlevel produced by the original dose of ketoconazole, whereby the patientis administered ketoconazole or itraconazole and an effective dose of aGRM and is not exposed to increased risk of ketoconazole or itraconazoletoxicity.

Accordingly, Applicant discloses herein a method for treating a patientsuffering from excess steroid levels, the patient receiving an originaldose of ketoconazole or itraconazole, said method comprising:

administering a first dose of a glucocorticoid receptor modulator (GRM)to the patient, wherein said first GRM dose is administeredconcomitantly with said dose of ketoconazole or itraconazole, wherebythe patient is administered an original dose of ketoconazole oritraconazole and a first dose of a GRM for reducing steroid levels oreffects in the patient. In embodiments of such methods, wherein saidfirst dose of GRM comprises an amount of the GRM that is effective toaid in reducing steroid levels or effects in the patient withoutsubstantially increasing the level of ketoconazole or itraconazole inthe blood of the patient above that level produced by the original doseof ketoconazole or itraconazole, whereby the patient is administeredketoconazole or itraconazole and an effective dose of a GRM and is notexposed to increased risk of ketoconazole or itraconazole toxicity. Inembodiments, the excess steroid comprises excess androgen. Inembodiments, the excess steroid comprises excess progestogen. Inembodiments, the excess steroid comprises excess estrogen. Inembodiments, the excess steroid comprises excess cortisol.

Accordingly, in further embodiments, Applicant discloses herein methodsfor treating a Cushing's syndrome patient, the patient receiving anoriginal dose of ketoconazole or itraconazole, said methods comprising:

administering a first dose of a glucocorticoid receptor modulator (GRM)to the patient, wherein said first GRM dose is administeredconcomitantly with said dose of ketoconazole or itraconazole, wherebythe patient is administered an original dose of ketoconazole oritraconazole and a first dose of a GRM for treating Cushing's syndrome.In embodiments of such methods, wherein said first dose of GRM comprisesan amount of the GRM that is effective to aid in the treatment ofCushing's syndrome without substantially increasing the level ofketoconazole or itraconazole in the blood of the patient above thatlevel produced by the original dose of ketoconazole or itraconazole,whereby the patient is administered ketoconazole or itraconazole and aneffective dose of a GRM and is not exposed to increased risk ofketoconazole or itraconazole toxicity.

In embodiments, Applicant discloses methods for treating a Cushing'ssyndrome patient who is receiving ketoconazole or itraconazoletreatment, said ketoconazole or itraconazole treatment comprisingadministering an original dose of ketoconazole or itraconazole to saidpatient, said method comprising: administering said original dose ofketoconazole or itraconazole to said patient; and administering a firstdose of a glucocorticoid receptor modulator (GRM) to the patient,wherein said first dose of GRM comprises an amount of said GRM that iseffective to aid in the treatment of Cushing's syndrome withoutsubstantially increasing the level of ketoconazole or itraconazole inthe blood of the patient above that level produced by the original doseof ketoconazole or itraconazole, whereby the patient is administeredketoconazole or itraconazole and a GRM for treating Cushing's syndromeand is not exposed to increased risk of ketoconazole or itraconazoletoxicity. In embodiments, said GRM is mifepristone. In embodiments, theoriginal dose of ketoconazole or itraconazole and the first dose of GRMare administered within a short time of each other. In embodiments, theoriginal dose of ketoconazole or itraconazole and the first dose of GRMare administered at substantially the same time. In embodiments, theoriginal dose of ketoconazole or itraconazole and the first dose of GRMare administered concomitantly. In embodiments, the GRM is mifepristone.

Thus, in embodiments of these methods, administration of theketoconazole or itraconazole and of the GRM comprises concomitantadministration of the original dose of ketoconazole or itraconazole andthe first dose of the GRM. In embodiments of concomitant administration,ketoconazole or itraconazole and the GRM are administered to the subjectsimultaneously. Such concomitant administration of a GRM may be by oraladministration; by intravenous administration; subcutaneousadministration; parenteral administration; intra-arterialadministration; nasal administration; topical administration; or byother routes of administration, or combinations thereof.

In embodiments of the methods disclosed herein, ketoconazole oritraconazole and the GRM are administered to the patient in a singlepill containing both the ketoconazole or itraconazole and the GRM, orare administered in a single liquid formulation containing both theketoconazole or itraconazole and the GRM. In embodiments, the GRM ismifepristone.

In embodiments of the methods disclosed herein, the first dose of theGRM is a dose selected from about 25 milligrams (mg), about 50 mg, about100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about1800 mg, and about 2000 mg. In embodiments, the dose of the GRM is adose of mifepristone selected from about 300 mg, about 600 mg, about 900mg, about 1200 mg, and about 1500 mg. In embodiments of the methodsdisclosed herein, the first dose of the GRM is a dose greater than 800mg of the GRM per day. In embodiments of the methods disclosed herein,the GRM is mifepristone, and the first dose of mifepristone is a dosegreater than 800 mg of mifepristone per day.

The methods disclosed herein include repeated administration of a GRM toa patient in need of treatment, including repeated concomitantadministration of ketoconazole or itraconazole and a GRM.

For example, in yet further embodiments, a second dose of GRM isadministered, wherein said second dose is administered after theadministration of the first dose of GRM. The second dose of GRM maycomprise about the same amount of said GRM as the first dose of the GRM;may comprise a greater amount of said GRM than the first dose of GRM; ormay comprise a smaller amount of GRM than the first dose of GRM. Inembodiments of these methods, the GRM is mifepristone.

The methods disclosed herein may further comprise:

administering a subsequent dose of ketoconazole or itraconazole and asecond dose of GRM, wherein said subsequent dose and said second doseare both administered after the administration of the first dose of theGRM. In embodiments, the second dose of GRM comprises about the sameamount of the GRM as the first dose of GRM, and the subsequent dose ofketoconazole or itraconazole comprises about the same amount ofketoconazole or itraconazole as the original dose of ketoconazole oritraconazole. In embodiments, the subsequent dose of ketoconazole oritraconazole comprises a lesser amount of ketoconazole or itraconazolethan the amount of the original dose of ketoconazole or itraconazole. Inembodiments of these methods, the GRM is mifepristone.

In embodiments, the second dose of GRM comprises a greater amount of theGRM than the amount of said first dose of the GRM. In embodiments, thesecond dose of GRM comprises a greater amount of the GRM than the amountof said first dose of the GRM, and the subsequent dose of ketoconazoleor itraconazole comprises about the same amount of ketoconazole oritraconazole as the original dose of ketoconazole or itraconazole. Inembodiments of these methods, the GRM is mifepristone.

In embodiments comprising repeated administration of a GRM to a patientin need of treatment, including repeated concomitant administration ofketoconazole or itraconazole and a GRM, ketoconazole or itraconazole andthe GRM may be administered simultaneously. In embodiments of suchmethods, the GRM may be mifepristone.

In embodiments, ketoconazole or itraconazole and a GRM are administeredto the patient in a single pill containing both ketoconazole and the GRMor itraconazole, or in a single liquid formulation containing bothketoconazole or itraconazole and the GRM. In embodiments, the GRM ismifepristone.

Further embodiments of the methods disclosed herein may include furthersteps, e.g., may comprise administration of a third dose of a GRM,wherein said third dose of the GRM is administered after theadministration of the second dose of the GRM. In embodiments, such athird dose of GRM comprises about the same amount of the GRM as thesecond dose of the GRM. In embodiments, such a third dose of GRMcomprises a greater amount of the GRM than the second dose of the GRM.In embodiments, such a third dose of GRM is administered after theadministration of the second dose of the GRM. In embodiments, such athird dose of GRM comprises about the same amount of GRM as the amountof said second dose of the GRM. In embodiments, such a third dose of GRMcomprises a lesser amount of the GRM than the amount of said second doseof the GRM. In embodiments, such a third dose of GRA comprises a greateramount of the GRM than the amount of said second dose of the GRM. Insuch embodiments, the GRM may be mifepristone.

In embodiments, methods disclosed herein comprise concomitantadministration of ketoconazole or itraconazole and a third dose of GRM.In embodiments of such concomitant administration, ketoconazole oritraconazole and the GRM are administered to the patient simultaneously.In embodiments of such concomitant administration, ketoconazole oritraconazole and the GRM are administered to the patient in a singlepill containing both ketoconazole or itraconazole and the GRM, or in asingle liquid formulation containing both ketoconazole or itraconazoleand the GRM. In embodiments, the GRM is mifepristone.

Embodiments of the methods disclosed herein comprise treatments forpatients suffering from Cushing's syndrome; in embodiments, theCushing's syndrome patient suffers from Cushing's Disease. Suchtreatments for Cushing's syndrome comprise concomitant administration ofketoconazole or itraconazole and a GRM to the patient.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the methodscomprise concomitant treatment of the patient with ketoconazole oritraconazole and with a glucocorticoid receptor modulator (GRM). Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, the methods compriseconcomitant treatment of the patient with ketoconazole or itraconazoleand a GRM, wherein the dose of ketoconazole or itraconazole administeredconcomitantly with the GRM is not reduced with respect to theketoconazole or itraconazole dose administered to the patient in theabsence of concomitant treatment with ketoconazole or itraconazole and aGRM. In embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole or itraconazole treatment, the methodscomprise concomitant treatment of the patient with a GRM andketoconazole or itraconazole. In embodiments, the GRM is mifepristone.

Applicant discloses herein methods for treating a Cushing's syndromepatient, the patient receiving an original dose of ketoconazole oritraconazole, said method comprising: administering a first dose of aglucocorticoid receptor modulator (GRM) to the patient, wherein saidfirst GRM dose is administered concomitantly with the dose ofketoconazole or itraconazole, whereby the patient is administered bothan original dose of ketoconazole or itraconazole and a first dose of aGRM for treating Cushing's syndrome. In embodiments, the patient suffersfrom Cushing's Disease.

In embodiments, Applicant discloses herein methods for treating aCushing's syndrome patient, the patient receiving an original dose ofketoconazole or itraconazole, the method comprising:

administering a first dose of a GRM to the patient, wherein the firstGRM dose is administered concomitantly with the dose of ketoconazole oritraconazole, whereby the patient is administered both an original doseof ketoconazole or itraconazole and a first dose of GRM for treatingCushing's syndrome. In embodiments, the patient suffers from Cushing'sDisease. In embodiments, the GRM is mifepristone.

In further embodiments of such methods, wherein said first dose of a GRMcomprises a GRM amount that is effective to aid in the treatment ofCushing's syndrome without substantially increasing the level ofketoconazole or itraconazole in the blood of the patient above thatlevel produced by said original dose of ketoconazole or itraconazole,whereby the patient is administered both ketoconazole or itraconazoleand an effective dose of a GRM and is not exposed to increased risk ofketoconazole or itraconazole toxicity. In embodiments, administration ofketoconazole or itraconazole and of the GRM comprises concomitantadministration of the original dose of ketoconazole or itraconazole andthe first dose of the GRM. In embodiments, administering a GRM comprisesoral administration of the GRM. In embodiments, ketoconazole oritraconazole and the GRM are administered to the patient simultaneously.In embodiments, ketoconazole or itraconazole and the GRM areadministered to the patient in a single pill containing bothketoconazole or itraconazole and the GRM, or in a single liquidformulation containing both ketoconazole or itraconazole and the GRM. Inembodiments, the GRM is mifepristone.

In embodiments of the methods disclosed herein, the first dose of theGRM is selected from about 25 mg, about 50 mg, about 100 mg, about 200mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 900mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about2000 mg, about 2100 mg, about 2400 mg, about 2700 mg, and about 3000 mg.In embodiments of the methods disclosed herein, the first dose of theGRM is a dose greater than 800 mg of the GRM per day. In embodiments ofthe methods disclosed herein, the first dose of the GRM is a dose ofmifepristone selected from about 1500 mg mifepristone, about 1200 mgmifepristone, about 900 mg mifepristone, about 600 mg mifepristone, andabout 300 mg mifepristone. In embodiments of the methods disclosedherein, the GRM is mifepristone, and the first dose of mifepristone is adose greater than 800 mg of mifepristone per day.

Further embodiments of the methods disclosed herein compriseadministering a second dose of GRM, wherein said second dose isadministered after the administration of the first dose of GRM. Inembodiments, the second dose of GRM comprises about the same amount ofsaid GRM as the first dose of the GRM. In embodiments, the second doseof GRM comprises a greater amount of said GRM than the first dose ofGRM. In embodiments, the GRM is mifepristone.

Further embodiments of the methods disclosed herein compriseadministering a subsequent dose of ketoconazole or itraconazole and asecond dose of GRM, wherein the subsequent ketoconazole or itraconazoledose and the second GRM dose are both administered after theadministration of the first dose of the GRM. In embodiments, the seconddose of GRM comprises about the same amount of the GRM as the first doseof the GRM, and the subsequent dose of ketoconazole or itraconazolecomprises about the same amount of ketoconazole or itraconazole as theoriginal dose of ketoconazole or itraconazole. In embodiments, thesubsequent dose of ketoconazole or itraconazole comprises a lesseramount of ketoconazole or itraconazole than the amount of the originaldose of ketoconazole or itraconazole. In embodiments, the second dose ofGRM comprises a greater amount of the GRM than the amount of said firstdose of the GRM. In embodiments, the second dose of GRA comprises agreater amount of the GRM than the amount of the first dose of the GRM,and the subsequent dose of ketoconazole or itraconazole comprises aboutthe same amount of ketoconazole or itraconazole as the original dose ofketoconazole or itraconazole. In embodiments, the GRM is mifepristone.

In embodiments, ketoconazole or itraconazole and the GRM areadministered to the patient simultaneously. In embodiments, ketoconazoleor itraconazole and mifepristone are administered to the patientsimultaneously. In embodiments, ketoconazole or itraconazole and the GRMare administered to the patient in a single pill containing bothketoconazole or itraconazole and the GRM, or in a single liquidformulation containing both ketoconazole or itraconazole and the GRM. Inembodiments, ketoconazole or itraconazole and mifepristone areadministered to the patient simultaneously. In embodiments, ketoconazoleor itraconazole and mifepristone are administered to the patient in asingle pill comprising both ketoconazole or itraconazole andmifepristone, or in a single liquid formulation comprising bothketoconazole or itraconazole and mifepristone.

Embodiments of the methods disclosed herein further compriseadministration of a third dose of GRM, wherein said third dose of theGRM is administered after the administration of the second dose of theGRM. In embodiments, the third dose of GRM comprises about the sameamount of the GRM as the second dose of the GRM. In embodiments, thethird dose of GRM comprises a greater amount of the GRM than the seconddose of the GRM. In embodiments, the methods further compriseadministration of a third dose of GRM, wherein the third dose of the GRMis administered after the administration of the second dose of the GRM.In embodiments, the third dose of GRM comprises about the same amount ofGRM as the amount of said second dose of the GRM. In embodiments, thethird dose of the GRM comprises a lesser amount of the GRM than theamount of said second dose of the GRM. In embodiments, the third dose ofGRM comprises a greater amount of the GRM than the amount of said seconddose of the GRM. In embodiments, administration of the third GRM dosecomprises concomitant administration ketoconazole and the third dose ofGRM. In such embodiments, ketoconazole and the GRM are administered tothe patient simultaneously. In embodiments of the methods comprisingsuch third dose of GRM, ketoconazole and the GRM are administered to thepatient in a single pill containing both ketoconazole and the GRM, or ina single liquid formulation containing both ketoconazole and the GRM. Inembodiments, the GRM is mifepristone.

Applicant discloses herein methods for treating Cushing's syndromepatients with a GRM (such as mifepristone) and ketoconazole oritraconazole. In embodiments, the patient suffers from Cushing'sDisease.

Applicant discloses here methods for treating a Cushing's syndromepatient who is receiving ketoconazole or itraconazole treatment, saidketoconazole or itraconazole treatment comprising administering anoriginal dose of ketoconazole or itraconazole to said patient, saidmethod comprising: administering said original dose of ketoconazole oritraconazole to said patient; and administering a glucocorticoidreceptor modulator (GRM) to the patient, wherein the amount of GRMadministered is a first dose of GRM, whereby the patient is administeredboth ketoconazole or itraconazole and a GRM for treating Cushing'ssyndrome. In embodiments, the first dose of GRM is a lesser amount ofGRM than would be administered in the absence of ketoconazole oritraconazole. In embodiments, the GRM is mifepristone.

In embodiments of such methods of treating a Cushing's syndrome patientwho is receiving ketoconazole or itraconazole treatment, the first doseof GRM comprises an amount of GRM that is effective to aid in thetreatment of Cushing's syndrome without substantially increasing thelevel of ketoconazole or itraconazole in the blood of the patient abovethat level produced by said original dose of ketoconazole oritraconazole, whereby the patient is administered both ketoconazole oritraconazole and an effective dose of a GRM and is not exposed toincreased risk of ketoconazole or itraconazole toxicity. In embodiments,the first dose of GRM is a lesser amount of GRM than would beadministered in the absence of ketoconazole or itraconazole. Inembodiments, the GRM is mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the administration of ketoconazoleor itraconazole and of the GRM comprises concomitant administration ofthe original dose of ketoconazole or itraconazole and the first dose ofsaid GRM. In embodiments of methods of treating a Cushing's syndromepatient who is receiving ketoconazole or itraconazole treatment, theadministration of the GRM comprises oral administration of the GRM. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, the ketoconazole oritraconazole and the GRM are administered to the patient simultaneously.In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the ketoconazole oritraconazole and the GRM are administered to the patient in a singlepill containing both ketoconazole or itraconazole and the GRM. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, ketoconazole oritraconazole and mifepristone are administered in a single liquidformulation comprising ketoconazole or itraconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the first dose ofthe GRM is a dose of GRM selected from about 25 mg, about 50 mg, about100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about1800 mg, about 2000 mg, about 2100 mg, about 2400 mg, about 2700 mg, andabout 3000 mg. In embodiments of the methods disclosed herein, the firstdose of the GRM is a dose greater than 800 mg of the GRM per day. Inembodiments, the GRM is mifepristone, and the first dose of the GRM is adose of mifepristone selected from about 1500 mg mifepristone, about1200 mg mifepristone, about 900 mg mifepristone, about 600 mgmifepristone, and about 300 mg mifepristone. In embodiments of themethods disclosed herein, the GRM is mifepristone, and the first dose ofmifepristone is a dose greater than 800 mg of mifepristone per day.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the methods furthercomprise: administering a second dose of GRM, wherein said second doseis administered after the administration of the first dose of said GRM.In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the second dose ofGRM comprises about the same amount of said GRM as the first dose of theGRM. In embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole or itraconazole treatment, the second doseof GRM comprises a lesser amount of said GRM than the first dose of GRM.In embodiments, the second dose of GRM is a lesser amount of GRM thanwould be administered in the absence of ketoconazole or itraconazole. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, the second dose of GRMcomprises a greater amount of said GRM than the first dose of GRM. Inembodiments, the GRM is mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the methods furthercomprise: administering a subsequent dose of ketoconazole oritraconazole and a second dose of GRM, wherein the subsequentketoconazole or itraconazole dose and the second GRM dose are bothadministered after the administration of the first dose of the GRM. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, the second dose of theGRM comprises about the same amount of the GRM as the first dose of theGRM, and the subsequent dose of ketoconazole or itraconazole comprisesabout the same amount of ketoconazole or itraconazole as the originaldose of ketoconazole or itraconazole. In embodiments, the second dose ofGRM is a lesser amount of GRM than would be administered in the absenceof ketoconazole or itraconazole.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the subsequent doseof ketoconazole or itraconazole comprises a lesser amount ofketoconazole or itraconazole than the amount of the original dose ofketoconazole or itraconazole. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoletreatment, the second dose of the GRM comprises a greater amount of theGRM than the amount of said first dose of the GRM. In embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole or itraconazole treatment, the second dose of the GRMcomprises a greater amount of the GRM than the amount of said first doseof the GRM, and said subsequent dose of ketoconazole or itraconazolecomprises about the same amount of ketoconazole or itraconazole as theoriginal dose of ketoconazole or itraconazole. In embodiments of methodsof treating a Cushing's syndrome patient who is receiving ketoconazoleor itraconazole treatment, the ketoconazole or itraconazole and the GRMare administered to the patient simultaneously. In embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole or itraconazole treatment, the ketoconazole or itraconazoleand the GRM are administered to the patient in a single pill containingboth ketoconazole or itraconazole and the GRM, or in a single liquidformulation comprising ketoconazole or itraconazole and the GRM. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole or itraconazole treatment, the GRM ismifepristone, and the ketoconazole or itraconazole and the mifepristoneare administered to the patient in a single pill comprising bothketoconazole or itraconazole and mifepristone, or in a single liquidformulation comprising ketoconazole or itraconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the methods furthercomprise: administration of a third dose of the GRM, wherein the thirddose of the GRM is administered after the administration of the seconddose of the GRM. In embodiments, the third dose of GRM is a lesseramount of GRM than would be administered in the absence of ketoconazole.In such embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole or itraconazole treatment, the third doseof GRM comprises about the same amount of the GRM as the second dose ofthe GRM. In such embodiments of methods of treating a Cushing's syndromepatient who is receiving ketoconazole or itraconazole treatment, thethird dose of the GRM comprises a greater amount of the GRM than thesecond dose of the GRM. In such embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoletreatment, the third dose of the GRM is administered after theadministration of the second dose of the GRM. In such embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole or itraconazole treatment, the third dose of the GRMcomprises about the same amount of GRM as the amount of said second doseof the GRM. In such embodiments of methods of treating a Cushing'ssyndrome patient who is receiving ketoconazole or itraconazoletreatment, the third dose of the GRM comprises a lesser amount of theGRM than the amount of said second dose of the GRM. In such embodimentsof methods of treating a Cushing's syndrome patient who is receivingketoconazole treatment, the third dose of the GRM comprises a greateramount of the GRM than the amount of said second dose of the GRM. Inembodiments, the GRM is mifepristone.

In such embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole or itraconazole treatment, the methodscomprise concomitant administration of ketoconazole or itraconazole andof the third dose of the GRM. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoletreatment, the ketoconazole or itraconazole and the GRM are administeredto the patient simultaneously. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoletreatment, the ketoconazole or itraconazole and the GRM are administeredto the patient in a single pill containing both ketoconazole oritraconazole and the GRM, or in a single liquid formulation comprisingketoconazole or itraconazole and the GRM. In embodiments of methods oftreating a Cushing's syndrome patient who is receiving ketoconazole oritraconazole treatment, the GRM is mifepristone, and the ketoconazole oritraconazole and the mifepristone are administered to the patient in asingle pill comprising both ketoconazole or itraconazole andmifepristone, or in a single liquid formulation comprising ketoconazoleor itraconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, the methodscomprise concomitant treatment of the patient with mifepristone andketoconazole or itraconazole. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoletreatment, the methods comprise concomitant treatment of the patientwith mifepristone and ketoconazole or itraconazole, wherein the dose ofketoconazole or itraconazole administered concomitantly withmifepristone is not reduced with respect to the ketoconazole oritraconazole dose administered to the patient in the absence ofconcomitant treatment with ketoconazole and mifepristone.

Applicant discloses herein a method for treating a Cushing's syndromepatient who is receiving ketoconazole or itraconazole treatment, saidketoconazole or itraconazole treatment comprising administering anoriginal dose of ketoconazole or itraconazole to said patient, saidmethod comprising: administering said original dose of ketoconazole oritraconazole to said patient; and administering mifepristone to thepatient, wherein the amount of mifepristone administered is a first doseof mifepristone, whereby the patient is administered both ketoconazoleor itraconazole and mifepristone for treating Cushing's syndrome. Inembodiments, the first dose of mifepristone is a lesser amount ofmifepristone than would be administered in the absence of ketoconazoleor itraconazole.

In embodiments of methods for treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment, wherein theketoconazole or itraconazole treatment comprises administering anoriginal dose of ketoconazole or itraconazole to said patient, themethods comprise administering a first dose of mifepristone thatcomprises an amount of mifepristone that is effective to aid in thetreatment of Cushing's syndrome without substantially increasing thelevel of ketoconazole or itraconazole in the blood of the patient abovethat level produced by said original dose of ketoconazole oritraconazole, whereby the patient is administered both ketoconazole oritraconazole and an effective dose of mifepristone and is not exposed toincreased risk of ketoconazole or itraconazole toxicity. In embodimentsof such methods, the administration of ketoconazole or itraconazole andof mifepristone comprises concomitant administration of the originaldose of ketoconazole or itraconazole and of the first dose ofmifepristone. In embodiments of such methods, the administration ofmifepristone comprises oral administration of mifepristone. Inembodiments of such methods, ketoconazole or itraconazole andmifepristone are administered to the patient simultaneously. Inembodiments of such methods, ketoconazole or itraconazole andmifepristone are administered to the patient in a single pill comprisingboth ketoconazole or itraconazole and mifepristone, or in a singleliquid formulation comprising ketoconazole or itraconazole andmifepristone. In embodiments of such methods, the first dose ofmifepristone is a dose of about 300 milligrams (mg), about 600 mg, about900 mg, about 1200 mg, or about 1500 mg. In embodiments of the methodsdisclosed herein, the first dose of mifepristone is a dose greater than800 mg of mifepristone per day.

In embodiments, such methods further comprise: administering a seconddose of mifepristone, wherein said second dose is administered after theadministration of the first dose of mifepristone. In embodiments, thesecond dose of mifepristone is a lesser amount of mifepristone thanwould be administered in the absence of ketoconazole or itraconazole. Inembodiments of such methods, the second dose of mifepristone comprisesabout the same amount of mifepristone as the first dose of mifepristone.In embodiments of such methods, the second dose of mifepristonecomprises a greater amount of mifepristone than the first dose ofmifepristone. In embodiments, such methods further compriseadministering a subsequent dose of ketoconazole or itraconazole and asecond dose of mifepristone, wherein said subsequent dose and saidsecond dose are both administered after the administration of the firstdose of mifepristone. In embodiments of such methods, the second dose ofmifepristone is a lesser amount of mifepristone than would beadministered in the absence of ketoconazole or itraconazole. Inembodiments of such methods, the second dose of mifepristone comprisesabout the same amount of mifepristone as the first dose of mifepristone,and said subsequent dose of ketoconazole or itraconazole comprises aboutthe same amount of ketoconazole or itraconazole as the original dose ofketoconazole or itraconazole. In embodiments of such methods, thesubsequent dose of ketoconazole or itraconazole comprises a lesseramount of ketoconazole or itraconazole than the amount of the originaldose of ketoconazole or itraconazole. In embodiments of such methods,the second dose of mifepristone comprises a greater amount ofmifepristone than the amount of said first dose of mifepristone. Inembodiments of such methods, the second dose of mifepristone comprises agreater amount of mifepristone than the amount of said first dose ofmifepristone, and said subsequent dose of ketoconazole or itraconazolecomprises about the same amount of ketoconazole or itraconazole as theoriginal dose of ketoconazole or itraconazole. In embodiments of suchmethods, ketoconazole or itraconazole and mifepristone are administeredto the patient simultaneously. In embodiments of such methods,ketoconazole or itraconazole and mifepristone are administered to thepatient in a single pill comprising both ketoconazole or itraconazoleand mifepristone, or in a single liquid formulation comprisingketoconazole or itraconazole and mifepristone.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole or itraconazole. In embodiments of such methods, the thirddose of mifepristone comprises about the same amount of mifepristone asthe second dose of mifepristone. In embodiments of such methods, thethird dose of mifepristone comprises a greater amount of mifepristonethan the second dose of mifepristone. In embodiments, such methodsfurther comprise administration of a third dose of mifepristone, whereinsaid third dose of mifepristone is administered after the administrationof the second dose of mifepristone. In embodiments of such methods, thethird dose of mifepristone comprises about the same amount ofmifepristone as the amount of said second dose of mifepristone. Inembodiments of such methods, the third dose of mifepristone comprises alesser amount of mifepristone than the amount of said second dose ofmifepristone. In embodiments of such methods, the third dose ofmifepristone comprises a greater amount of mifepristone than the amountof said second dose of mifepristone. In embodiments, such methodscomprise concomitant administration of ketoconazole or itraconazole andof the third dose of mifepristone. In embodiments of such methods,ketoconazole or itraconazole and mifepristone are administered to thepatient simultaneously. In embodiments of such methods, ketoconazole oritraconazole and mifepristone are administered to the patient in asingle pill comprising both ketoconazole or itraconazole andmifepristone, or in a single liquid formulation comprising ketoconazoleor itraconazole and mifepristone.

In embodiments of methods for treating a Cushing's syndrome patient whois receiving ketoconazole or itraconazole treatment at an original doseof ketoconazole or itraconazole, the methods comprise administering afirst dose of mifepristone to the subject and reducing the dose ofketoconazole or itraconazole received by the patient to a ketoconazoleor itraconazole dose that is less than the original ketoconazole oritraconazole dose, wherein the dose of mifepristone comprises an amountof mifepristone that is effective to aid in the treatment of Cushing'ssyndrome without substantially increasing the level of ketoconazole oritraconazole in the blood of the patient above that level produced bysaid original dose of ketoconazole or itraconazole, whereby the patientis administered both ketoconazole or itraconazole and an effective doseof mifepristone and is not exposed to increased risk of ketoconazole oritraconazole toxicity.

Accordingly, Applicant discloses herein a method for treating aCushing's syndrome patient who is receiving ketoconazole or itraconazoleat an initial dosage, said initial dosage comprising administering aninitial dose of ketoconazole or itraconazole to said patient, saidmethod comprising: administering a reduced dose of ketoconazole oritraconazole to said patient, wherein said reduced dose of ketoconazoleor itraconazole is a dose of ketoconazole or itraconazole that is lessthan said initial dose by an amount of at least about 5% of the initialdose; and administering mifepristone to the patient, wherein the amountof mifepristone administered is a first dose of mifepristone, wherebythe patient is administered both the reduced dose of ketoconazole oritraconazole and the first dose of mifepristone. In embodiments of suchmethods, the first dose of mifepristone comprises an amount ofmifepristone that is effective to aid in the treatment of Cushing'ssyndrome, whereby the patient is administered both a reduced dose ofketoconazole and an effective dose of mifepristone. In embodiments, thefirst dose of mifepristone is a lesser amount of mifepristone than wouldbe administered in the absence of ketoconazole. In embodiments of suchmethods, the administration of ketoconazole or itraconazole and ofmifepristone comprises concomitant administration of the reduced dose ofketoconazole or itraconazole and the first dose of mifepristone. Inembodiments of such methods, the administration of mifepristonecomprises oral administration of mifepristone. In embodiments of suchmethods, the first dose of ketoconazole or itraconazole is less thansaid initial dose of ketoconazole or itraconazole by an amount that isabout 10%, about 15%, about 25%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 60%, about 75%, or about 90% less thanthe initial dose. In embodiments of such methods, the first dose ofmifepristone is a dose selected from about 300 mg, about 600 mg, about900 mg, about 1200 mg, and about 1500 mg.

In embodiments, such methods further comprise administering a seconddose of mifepristone, wherein said second dose is administered at a timeafter the administration of the first dose of mifepristone. Inembodiments, the second dose of mifepristone is a lesser amount ofmifepristone than would be administered in the absence of ketoconazole.In embodiments of such methods, the second dose of mifepristonecomprises a lesser amount of mifepristone than the first dose ofmifepristone. In embodiments of such methods, the second dose ofmifepristone comprises about the same amount of mifepristone as thefirst dose of mifepristone. In embodiments of such methods, the seconddose of mifepristone comprises a greater amount of mifepristone than thefirst dose of mifepristone. In embodiments, such methods furthercomprise administering a subsequent dose of ketoconazole or itraconazoleand a second dose of mifepristone, wherein said subsequent dose and saidsecond dose are both administered at a time after the administration ofboth the reduced dose of ketoconazole or itraconazole and of the firstdose of mifepristone. In embodiments of such methods, the second dose ofmifepristone comprises about the same amount of mifepristone as thefirst dose of mifepristone, and said subsequent dose of ketoconazole oritraconazole comprises about the same amount of ketoconazole oritraconazole as the reduced dose of ketoconazole or itraconazole. Inembodiments of such methods, the subsequent dose of ketoconazole oritraconazole comprises a lesser amount of ketoconazole or itraconazolethan the amount of said reduced dose of ketoconazole or itraconazole. Inembodiments of such methods, the second dose of mifepristone comprises agreater amount of mifepristone than the amount of said first dose ofmifepristone. In embodiments of such methods, the second dose ofmifepristone comprises a greater amount of mifepristone than the amountof said first dose of mifepristone, and said subsequent dose ofketoconazole or itraconazole comprises about the same amount ofketoconazole or itraconazole as the reduced dose of ketoconazole oritraconazole.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered at a time after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole or itraconazole. In embodiments of such methods, the thirddose of mifepristone comprises a lesser amount of mifepristone than thesecond dose of mifepristone. In embodiments of such methods, the thirddose of mifepristone comprises about the same amount of mifepristone asthe second dose of mifepristone. In embodiments of such methods, thethird dose of mifepristone comprises a greater amount of mifepristonethan the second dose of mifepristone.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered at a time after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole or itraconazole. In embodiments of such methods, the thirddose of mifepristone comprises about the same amount of mifepristone asthe amount of said second dose of mifepristone. In embodiments of suchmethods, the third dose of mifepristone comprises a lesser amount ofmifepristone than the amount of said second dose of mifepristone. Inembodiments of such methods, the third dose of mifepristone comprises agreater amount of mifepristone than the amount of said second dose ofmifepristone. In embodiments, such methods comprise administration of adose of ketoconazole or itraconazole administered at the time as theadministration of the third dose of mifepristone.

Applicant further discloses herein methods for treating a patient who issuffering from Cushing's syndrome with mifepristone, the patient alsoreceiving concomitant administration of ketoconazole or itraconazole,said method comprising: to the patient concomitantly receivingketoconazole or itraconazole, orally administering a dose ofmifepristone that is a smaller dose of mifepristone than the dose thatis an effective mifepristone dose when the patient receives onlymifepristone. An effective dose of mifepristone when the patientreceives only mifepristone for treating Cushing's syndrome is termed a“lone dose” of mifepristone. For example, the dose of mifepristone thatis effective for the treatment of a Cushing's syndrome patient notconcomitantly receiving ketoconazole or other treatment for Cushing'ssyndrome is a “lone dose” of mifepristone. In embodiments of the methodsdisclosed herein, for Cushing's syndrome patient receiving concomitantadministration of ketoconazole or itraconazole, the dose of mifepristoneis reduced by at least about 5% as compared to the lone dose ofmifepristone. Accordingly, Applicant discloses herein a method fortreating a Cushing's syndrome patient who is receiving ketoconazole oritraconazole, said method comprising: administering a reduced dose ofmifepristone to said patient, wherein said reduced dose of mifepristoneis a dose of mifepristone that is less than the lone dose ofmifepristone as defined herein; whereby the patient is administered bothketoconazole or itraconazole and the reduced dose of mifepristone. Inembodiments, such a reduced dose of mifepristone is an amount ofmifepristone that is less than the lone dose of mifepristone by anamount that is at least about 5% of the lone dose. In embodiments ofsuch methods, the reduced dose of mifepristone comprises an amount ofmifepristone that is effective to aid in the treatment of Cushing'ssyndrome, whereby the patient is administered both a reduced dose ofmifepristone and a dose of ketoconazole or itraconazole. In embodimentsof such methods, the administration of ketoconazole or itraconazole andof mifepristone comprises concomitant administration of the reduced doseof mifepristone and the dose of ketoconazole or itraconazole. Inembodiments of such methods, the administration of mifepristonecomprises oral administration of mifepristone. In embodiments of suchmethods, the reduced dose of mifepristone is less than said lone dose ofmifepristone by an amount that is about 10%, about 15%, about 25%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%,about 75%, or about 90% less than the lone dose. In embodiments of suchmethods, the reduced dose of mifepristone is a daily dose selected fromabout 900 mg, greater than 800 mg, about 600 mg, about 300 mg, or is adose of mifepristone selected from about 300 mg mifepristoneadministered every other day, a dose of about 300 mg mifepristoneadministered every third day, and a dose of mifepristone of about 300 mgadministered every fourth day.

Compositions

Applicant discloses herein compositions comprising a glucocorticoidreceptor modulator (GRM), such as a glucocorticoid receptor antagonist(GRA) such as, e.g., mifepristone, which may be used in the treatment ofa patient suffering from excess cortisol, e.g., in a patient sufferingfrom Cushing's syndrome. In embodiments, the compositions comprising aGRM may be provided in an amount effective to control hyperglycemiasecondary to hypercortisolism, and may be provided in an amounteffective control hyperglycemia secondary to hypercortisolism in apatient suffering from endogenous Cushing's disease. In embodiments, thecompositions comprising a GRM may be provided in an amount effective tocontrol hyperglycemia secondary to hypercortisolism in a patientsuffering from endogenous Cushing's disease, where the patient hasfailed surgery, or is not a candidate for surgery.

Applicant also discloses herein compositions comprising a GRM andketoconazole or itraconazole. These compositions comprising a GRM andketoconazole or itraconazole may be used in the treatment of a Cushing'ssyndrome patient.

The compositions as disclosed herein can be prepared in a wide varietyof oral, parenteral and topical dosage forms. Oral preparations includetablets, pills, powder, dragees, capsules, liquids, lozenges, cachets,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. The compositions of the present invention can also beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compositions disclosed herein can be administered byinhalation, for example, intranasally. Additionally, the compositions ofthe present invention can be administered transdermally. Thecompositions disclosed herein can also be administered by intraocular,intravaginal, and intrarectal routes including suppositories,insufflation, powders and aerosol formulations (for examples of steroidinhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa,Ann. Allergy Asthma Immunol. 75:107-111, 1995).

In embodiments disclosed herein, the compositions include pharmaceuticalcompositions including a pharmaceutically acceptable carrier orexcipient, a GRM, and a CYP3A inhibitor. CYP3A inhibitors include, forexample, strong CYP3A inhibitors such as ketoconazole, itraconazole,nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir andfosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir,posaconazole, saquinavir, telithromycin, and voriconazole. Inembodiments disclosed herein, the compositions include pharmaceuticalcompositions including a pharmaceutically acceptable carrier orexcipient, a GRM, and a steroidogenesis inhibitor (SI). SIs include, forexample, ketoconazole, levoketoconazole, metyrapone, aminoglutethimide,etomidate, LCI699 (Osilodrostat), and others.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Mack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of ketoconazole or itraconazole and/or the GRM.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can containketoconazole and/or the GRM mixed with a filler or binders such aslactose or starches, lubricants such as talc or magnesium stearate, and,optionally, stabilizers. In soft capsules, ketoconazole and/or the GRMmay be dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycol with or withoutstabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and ketoconazoleand/or the GRM are dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingketoconazole and/or the GRM in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partialester derived from a fatty acid and a hexitol (e.g., polyoxyethylenesorbitol mono-oleate), or a condensation product of ethylene oxide witha partial ester derived from fatty acid and a hexitol anhydride (e.g.,polyoxyethylene sorbitan mono-oleate). The aqueous suspension can alsocontain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose, aspartame orsaccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending ketoconazole and/or theGRA in a vegetable oil, such as arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin; or a mixtureof these. The oil suspensions can contain a thickening agent, such asbeeswax, hard paraffin or cetyl alcohol. Sweetening agents can be addedto provide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations of the invention can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan mono-oleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

The compositions of the present invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe formulated for administration via intradermal injection ofdrug-containing microspheres, which slowly release subcutaneously (seeRao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable andinjectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months.

In another embodiment, the compositions of the present invention can beformulated for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

Administration

The compositions disclosed herein can be delivered by any suitablemeans, including oral, parenteral and topical methods. Transdermaladministration methods, by a topical route, can be formulated asapplicator sticks, solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, and aerosols.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the GRM and ketoconazole. In embodiments, theGRM is mifepristone. The unit dosage form can be a packaged preparation,the package containing discrete quantities of preparation, such aspacketed tablets, capsules, and powders in vials or ampoules. Also, theunit dosage form can be a capsule, tablet, cachet, or lozenge itself, orit can be the appropriate number of any of these in packaged form.

The GRM and CYP3A inhibitor or steroidogenesis inhibitor can beco-administered or administered separately The GRM and ketoconazole oritraconazole can be co-administered or administered separately.Concomitant administration includes administering the CYP3A inhibitor orsteroidogenesis inhibitor within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or24 hours of the GRM. Concomitant administration also includesadministering the GRM and the CYP3A inhibitor or steroidogenesisinhibitor simultaneously, approximately simultaneously (e.g., withinabout 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially inany order. Moreover, the GRM and the CYP3A inhibitor or steroidogenesisinhibitor can each be administered once a day, or two, three, or moretimes per day so as to provide the preferred dosage level per day. Inembodiments, the GRM is mifepristone.

In some embodiments, concomitant administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both the GRM and the CYP3A inhibitor or steroidogenesisinhibitor. Suitable co-formulations include single pharmaceuticalcompositions including a GRM, the CYP3A inhibitor or steroidogenesisinhibitor, and a pharmaceutically acceptable excipient. In embodiment,the GRM is mifepristone.

In other embodiments, the GRM and the CYP3A inhibitor or steroidogenesisinhibitor can be formulated separately.

The CYP3A inhibitor or steroidogenesis inhibitor can be present in anysuitable amount, and can depend on various factors including, but notlimited to, weight and age of the subject, state of the disease, etc.Suitable dosage ranges for the CYP3A inhibitor or steroidogenesisinhibitor in combination with the GRM, include from about 0.1 mg toabout 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg.Suitable dosages for the CYP3A inhibitor or steroidogenesis inhibitor incombination with the GRM, include about 1 mg, 5, 10, 20, 30, 40, 50, 60,70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. Inembodiments, the GRM is mifepristone.

Similarly, the GRM can be present in combination with the CYP3Ainhibitor or steroidogenesis inhibitor in any suitable amount. Theamount of GRM can depend on various factors including, but not limitedto, weight and age of the subject, state of the disease, etc. Suitabledosage ranges for the GRM in combination with the CYP3A inhibitor orsteroidogenesis inhibitor include from about 0.1 mg to about 10,000 mg,or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosagesfor the GRM in combination with the CYP3A inhibitor or steroidogenesisinhibitor include, but are not limited to, about 1 mg, 5, 10, 20, 30,40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 orabout 1000 mg. In embodiments, the GRM is mifepristone,

The CYP3A inhibitor or steroidogenesis inhibitor and the GRM can bepresent in the compositions of the present invention in any suitableweight ratio, such as from about 1:100 to about 100:1 (w/w), or about1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about10:1, or about 1:5 to about 5:1 (w/w). The CYP3A inhibitor orsteroidogenesis inhibitor and the GRM can be present in any suitableweight ratio, such as about 1:100 (w/w), 1:50, 1:25, 1:10, 1:5, 1:4,1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1 or 100:1 (w/w).Other dosages and dosage ratios of ketoconazole and the GRM are suitablein the compositions and methods disclosed herein. In embodiments, theGRM is mifepristone.

The composition can also contain other compatible therapeutic agents.The compounds described herein can be used in combination with oneanother, or with adjunctive agents that may not be effective alone, butmay contribute to the efficacy of the active agent.

Kits

Applicant further provides kits including compositions as disclosedherein. Kits may also include instructions for the use of thecompositions.

In embodiments, a kit includes: a pharmaceutical composition containinga CYP3A inhibitor or steroidogenesis inhibitor (e.g. ketoconazole oritraconazole) and a pharmaceutical composition containing a GRM. Inembodiments, the GRM is mifepristone.

In embodiments, a kit includes: a pharmaceutical composition containinga CYP3A inhibitor or steroidogenesis inhibitor; and a pharmaceuticalcomposition containing a GRM; and instructions for the use (e.g.,administration) of the CYP3A inhibitor or steroidogenesis inhibitor andthe GRM. In embodiments, the GRM is mifepristone, and the instructionsinclude instructions for the administration of mifepristone. Inembodiments, the instructions include instructions regarding one or moreof the number of pharmaceutical compositions to be taken each day, thetiming of such administration, whether or not the pharmaceuticals are tobe taken with food or in a fasted state, contraindications, possibleside effects, activities to be avoided during treatment with thepharmaceutical compositions (if any), and foods to be avoided duringtreatment with the pharmaceutical compositions (if any).

In embodiments, a kit includes: a pharmaceutical composition containinga CYP3A inhibitor or steroidogenesis inhibitor and a GRM. Inembodiments, the GRM is mifepristone, and the pharmaceutical compositioncontains ketoconazole and mifepristone.

In embodiments, a kit includes: a pharmaceutical composition containinga CYP3A inhibitor or steroidogenesis inhibitor and a GRM; andinstructions for the use (e.g., administration) of the pharmaceuticalcomposition. In embodiments, the GRM is mifepristone. In embodiments ofthe kits disclosed herein, the pharmaceutical composition includes CYP3Ainhibitor or steroidogenesis inhibitor and mifepristone, and theinstructions include instructions for the administration of thepharmaceutical containing a CYP3A inhibitor or a steroidogenesisinhibitor and mifepristone. In embodiments, the instructions includeinstructions regarding one or more of the number of pharmaceuticalcompositions to be taken each day, the timing of such administration,whether or not the pharmaceutical composition is to be taken with foodor in a fasted state, contraindications, possible side effects,activities to be avoided during treatment with the pharmaceuticalcomposition (if any), and foods to be avoided during treatment with thepharmaceutical composition (if any).

EXAMPLES

The following examples are presented by way of illustration ofembodiments of the methods disclosed herein, and serve to illustrate,but not to limit, the present disclosure of methods of treating patientssuffering from Cushing's syndrome, including Cushing's Disease; or fromprostate cancer and other androgen-sensitive cancers; or from breastcancer, ovarian cancer, or other cancer hormone-sensitive cancer (e.g.,cancer sensitive to estrogen or progesterone); and patients sufferingfrom other diseases, disorders, or syndromes.

Example 1

A study was performed in order to determine the effect of oralketoconazole at a dose of 400 mg once per day (OD) or 200 mg twice perday (BID) on the plasma pharmacokinetics of a 300 mg single dose ofmifepristone given to a fasted subject, in comparison to previous studydata. This study was an open-label study in healthy male subjects.

Healthy male volunteers between the ages of 18 to 45 years of age with abody mass index (BMI) ranging between 19 and 32 kg/m2 and a weight of atleast 60 kg (132 lbs) were enrolled. Subjects had no clinicallysignificant abnormal findings on the physical examination, ECG, bloodpressure, heart rate, medical history, or clinical laboratory resultsduring screening. The QTc interval at screening was less than 450 msec.

In cohort 1, six subjects received ketoconazole 400 mg OD for 14 days.The cohort 1 subjects participated in a screening visit to assesseligibility, and in a check-in day during which eligibility wasre-confirmed and the first dose of 400 mg oral ketoconazole given atapproximately 8 PM (12 hours prior to expected time of Day 1mifepristone dose).

The morning of Day 1, subjects received 400 mg oral ketoconazole fasted,0.5 hour prior to receiving the 300 mg single dose of mifepristonefasted. Subjects remained in the clinic on Days 2 and 3 to receive 400mg OD oral ketoconazole fasted, and for safety evaluation and collectionof blood pharmacokinetic (PK) samples. Subjects were discharged from theclinic on Day 4 following administration of 400 mg OD oral ketoconazolefasted, and returned to the clinic the mornings of Days 5 through 13 toreceive 400 mg OD oral ketoconazole fasted.

In cohort 2, six subjects received ketoconazole 200 mg BID for 14 days.The 300 mg single dose of mifepristone was given to all subjects onday 1. All 12 subjects completed the study. Cohort 2 subjectsparticipated in a Screening visit to assess eligibility and a check-inDay (Day −1) during which eligibility was re-confirmed. On Day 0,subjects received 200 mg BID oral ketoconazole: the morning dose afteran overnight fast and the evening dose 12 hours prior to expected timeof Day 1 Mifepristone dose. The morning of Day 1, subjects received 200mg oral ketoconazole fasted, 0.5 hour prior to receiving the 300 mgsingle dose of Mifepristone fasted. The evening of Day 1, subjectsreceived 200 mg oral ketoconazole. Subjects remained in the clinic onDays 2, 3 and 4 to receive 200 mg BID oral ketoconazole, and for safetyevaluation and collection of blood pharmacokinetic (PK) samples.Subjects were discharged from the clinic on Day 4 following eveningadministration of 200 mg oral ketoconazole, and returned to the clinicthe morning and evening of Days 5 through 13 to receive 200 mg BID oralketoconazole. Morning doses of ketoconazole on Days 0-13 wereadministered in the fasted state.

Subjects in both cohorts had blood sampling for determination of plasmaconcentrations of mifepristone and its metabolites within 30 minutesbefore mifepristone dosing and at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36,48, 60, 72 (Day 4), 120 (Day 6), 192 (Day 9), 264 (Day 12), and 336 (Day15) post mifepristone dose. Subjects in both cohorts returned to thestudy center on Day 15 for safety monitoring, and completion of theTermination Visit procedures, followed by discharge from the study.Safety was assessed by spontaneously reported adverse events, physicalexaminations, and routine clinical laboratory tests. To the extentpossible, any adverse events deemed study drug-related and that wereongoing at the time of discharge from the study were followed-up toresolution or until a determination is made that the unresolved eventwas stable.

No subject experienced a serious adverse effect (SAE), or an adverseevent (AE) that resulted in discontinuation from the study. Threesubjects (25%) experienced at least 1 treatment-emergent adverse event(TEAE). All TEAEs were mild in intensity. No TEAE was considered by theinvestigator to be related to mifepristone. One TEAE of insomnia wasconsidered by the investigator to be related to ketoconazole.

Minimal changes in laboratory test results were observed during thecourse of the study. No laboratory test result was considered by theinvestigator to be a TEAE. Any abnormal values or shifts from baselinewere considered not clinically significant. No clinically significantchanges in any electrocardiogram (ECG) parameter were observed.

Pharmacokinetics (PK): Blood samples were drawn within 30 minutes beforemifepristone dosing and at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60,72 (Day 4), 120 (Day 6), 192 (Day 9), 264 (Day 12), and 336 (Day 15)post mifepristone dose. Pharmacokinetic parameters were calculated forplasma concentrations of mifepristone and its metabolites following thesingle dose at Day 1. Descriptive statistics (count, mean, median,standard deviation, minimum, maximum, and % coefficient of variation)were provided. Mifepristone/metabolite concentrations were listed andsummarized. Comparisons with previous study data were made. The mean PKparameters from this study are presented in Table 1 (“MIFE” indicatesmifepristone). The abbreviations and symbols used in Table 1 have thefollowing meanings: “Tmax” indicates time to maximum observed plasmaconcentration; “Tmin” indicates time to minimum observed concentrationwithin the 24 hour dosing interval; “C_(max)” indicates maximum observedplasma concentration; “C_(min)” indicates minimum observed concentrationwithin the 24 hour dosing interval; “C_(avg)” indicates averagesteady-state concentration and is defined as drug input rate (Ro)divided by drug removal rate (CLss) (C_(avg)=Ro/CLss, where f (thefraction absorbed) cancels out (f is a factor of both Ro and CLss); thisequation reduces to C_(avg)=AUCtau/tau); “AUC₀₋₂₄” indicates area underthe plasma concentration versus time curve from time 0 to 24 hourspost-dose, calculated using the linear trapezoidal rule (this is thesame as AUCtau where tau is 24 hours or 1 day); “% Fluct” indicatespercent fluctuation in drug concentrations at steady-state computed as %Fluct=100×(C_(max)−C_(min))/C_(avg).

PHARMACOKINETIC (PK) RESULTS: Mifepristone plasma concentrations showeda rapid initial decline followed by a slow decline over time. At latertime points, concentrations showed an accelerated decline indicative ofnon-linear kinetics. Metabolites peaked later relative to parentmifepristone as would be expected. Mifepristone metabolite RU 42633exposure was similar or even greater than that for mifepristone, whileRU 42698 (a mifepristone metabolite) exposure was approximately 0.74 to0.94 relative to mifepristone and RU 42848 (also a mifepristonemetabolite) exposure was 0.53 to 0.68 relative to mifepristone. Withincrease in time interval, the fraction of AUC relative to mifepristoneaccounted for by metabolite increased.

Cohort 2 C_(max) (where C_(max) is the maximum observed plasmaconcentration) and AUCinf (where AUCinf is the area under theconcentration-time curve from time of last dose to infinity) weresimilar to corresponding parameters in Cohort 1. The geometric meanratio (GMR) for C_(max) was 1.15 and that for AUCinf was 1.05. However,the 90% confidence intervals around the GMR were higher than thestandard 80:125 reference interval. Thus, there may be a small increasein mifepristone exposure with a divided ketoconazole dose (200 mg BIDvs. 400 mg OD), but this was minor. Terminal half-life was approximatelythe same in Cohort 2 versus Cohort 1 and Tmax was shorter for Cohort 2versus Cohort 1.

SAFETY RESULTS: Among 12 subjects who received mifepristone, 3 (25%)experienced at least one treatment emergent adverse event (TEAE). AllTEAEs were mild in intensity. No TEAE was considered by the investigatorto be related to Mifepristone. One TEAE of insomnia was considered bythe investigator to be related to ketoconazole. No subject experiencedan SAE or an AE that resulted in discontinuation from the study. Minimalchanges in laboratory test results were observed for subjects during thecourse of the study. No laboratory test result was considered by theinvestigator to be a TEAE. Any abnormal values or shifts from Baselinevalues were considered not clinically significant. No clinicallysignificant changes in any ECG parameter were observed.

While PK parameters in Cohort 2 were similar to those in Cohort 1, the90% confidence intervals around the GMR were higher than the standard80:125 reference interval used for bioequivalence testing. Thus, theremay be a small and minor increase in mifepristone exposure with adivided ketoconazole dose (200 mg BID vs. 400 mg OD). Terminal half-lifewas approximately the same in Cohort 2 versus Cohort 1 and Tmax wasshorter for Cohort 2 versus Cohort 1. Mifepristone 300 mg was safe andwell tolerated in healthy volunteers under the following treatmentregimens: single-dose fasted with ketoconazole 400 mg OD for 14 days orketoconazole 200 mg BID for 14 days.

Example 2

The primary objective of this study was to determine the effect of a 400mg single dose of ketoconazole on the PK of an 8-day regimen of 300 mgor 600 mg OD mifepristone given following a moderate fat (34%)breakfast. This was an open-label study in healthy male subjects. Incohort 1, six subjects received mifepristone 300 mg OD for 8 days. Incohort 2, six subjects received mifepristone 600 mg OD for 8 days. The400 mg single dose of ketoconazole was given to all subjects on day 8.Three subjects discontinued early from the study: one subject in cohort1 due to new onset sinus bradycardia, and two subjects in cohort 2 dueto withdrawn consent.

METHODOLOGY: Twelve subjects were enrolled, six in Cohort 1 and 6 inCohort 2. Three subjects discontinued early from the study, one subjectin Cohort 1 due to an adverse event of sinus bradycardia, and twosubjects in Cohort 2 due to withdrawn consent.

Cohort 1: Subjects participated in a Screening visit to assesseligibility, and returned to the clinic on Days 1-6 to receive 300 mgoral mifepristone following a moderate fat breakfast. On Day 7 subjectswere admitted to the clinic in the fasted state for a pre-dose PK blooddraw, after which they received 300 mg oral mifepristone following amoderate fat breakfast. Subjects had serial blood sampling fordetermination of mifepristone and its metabolites at hours 0.5, 1, 2, 4,6, 8, and 12 post Day 7 dose. On Day 8, a pre-dose PK sample was drawnwithin 30 minutes prior to ketoconazole dosing for determination ofplasma concentrations of mifepristone and its metabolites andketoconazole. Following a moderate fat breakfast on Day 8, subjectsreceived 400 mg ketoconazole 0.5 hours prior to 300 mg mifepristone andhad serial blood sampling at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48,60, 72, and 120 post mifepristone dose for determination of plasmaconcentrations of mifepristone and its metabolites; and at hours 0.5, 1,1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 post ketoconazole dose fordetermination of plasma concentrations of ketoconazole. Subjects weredischarged on Day 11.

Cohort 2: Subjects participated in a Screening visit to assesseligibility and returned to the clinic on Days 1-6 to receive 600 mgoral mifepristone following a moderate fat breakfast. On Day 7 subjectswere admitted to the clinic in the fasted state for a pre-dose PK blooddraw, after which they received 600 mg oral mifepristone following amoderate fat breakfast. Subjects had serial blood sampling fordetermination of mifepristone and its metabolites at hours 0.5, 1, 2, 4,6, 8, and 12 post Day 7 dose. On Day 8, a pre-dose PK sample was drawnwithin 30 minutes prior to ketoconazole dosing for determination ofplasma concentrations of mifepristone and its metabolites andketoconazole. Following a moderate fat breakfast on Day 8, subjectsreceived 400 mg ketoconazole 0.5 hours prior to 600 mg mifepristone andhad serial blood sampling at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48,60, 72, and 120 post mifepristone dose for determination of plasmaconcentrations of mifepristone and its metabolites; and at hours 0.5, 1,1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 post ketoconazole dose fordetermination of plasma concentrations of ketoconazole. Subjects weredischarged on Day 11. Subjects in both cohorts returned to study centeron Day 13 for safety monitoring, collection of the 120-hour PK draw, andcompletion of the Termination Visit procedures, followed by dischargefrom the study. To the extent possible, any adverse events deemed studydrug-related and that were ongoing at the time of discharge from thestudy were followed-up to resolution or until a determination was madethat the unresolved event was stable.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Healthy male volunteersbetween the ages of 18 to 45 years of age with a body mass index (BMI)ranging between 19 and 32 kg/m2 and a weight of at least 60 kg (132 lbs)were enrolled. Subjects had no clinically significant abnormal findingson the physical examination, ECG, blood pressure, heart rate, medicalhistory, or clinical laboratory results during screening. The QTcinterval at screening was less than 450 msec.

DURATION OF TREATMENT: Up to a total of 28 days, including up to 2 weeksscreening, dosing on Days 1-8, safety observation, and PK samplecollection through Day 13. For measuring the pharmacokinetics ofmifepristone, samples were collected within 30 minutes before Day 7mifepristone dose and at hours 0.5, 1, 2, 4, 6, 8, and 12 post Day 7mifepristone dose; within 30 minutes before Day 8 ketoconazole dosingand at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, and 120 postDay 8 mifepristone dose. For measuring the pharmacokinetics ofketoconazole, samples were collected predose on Day 8 (24 hr sample fromDay 7), and at hours 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48hours post ketoconazole dose.

Safety was assessed by spontaneously reported adverse events, physicalexaminations, and routine clinical laboratory tests. Adverse event datawere tabulated. Physical findings and laboratory test results werelisted by subject.

SAFETY RESULTS: No subject experienced an SAE. Among twelve subjects whoreceived mifepristone, six subjects (50%) experienced at least 1 TEAE.TEAEs were predominantly mild in intensity. The majority of subjects(5/6) with TEAEs were in Cohort 2 and onset of the majority of TEAEsoccurred on or after Day 8 during treatment with both ketoconazole andmifepristone 600 mg. TEAEs considered possibly or probably related tomifepristone administration in four subjects in Cohort 2 were dizziness,nausea, vomiting, dry mouth, and rash. One TEAE of headache wasconsidered by the investigator to be possibly related to bothketoconazole and mifepristone administration. One subject in Cohort 1with a TEAE of nodal arrhythmia on Day 8 was withdrawn by theinvestigator. The event was considered mild in severity and notconsidered related to study medication. The corresponding ECGabnormality noted as “sinus bradycardia” was considered not clinicallysignificant. No subject experienced an SAE.

Minimal changes in laboratory test results were observed for subjectsduring the course of the study. No laboratory test result was consideredby the investigator to be a TEAE. There were no clinically significantchanges or abnormalities in vital signs, physical examinations or bodyweights during the study. Abnormal ECGs occurred in four subjects and noabnormality was considered clinically significant.

STATISTICAL METHODS: Pharmacokinetics (PK): Pharmacokinetic parametersC_(max), C_(trough), and interdosing interval AUC were calculated forplasma concentrations of mifepristone and its metabolites following doseon Days 7 and 8. Descriptive statistics (count, mean, median, standarddeviation, minimum, maximum, and % coefficient of variation) wereprovided. mifepristone/metabolite concentrations were listed andsummarized. GM means of C_(max) and AUC₀₋₂₄ were compared for Day 8 toDay 7 in this study and also to combined data of 300 mg OD mifepristonein previous multiple dose studies. Additionally, comparisons were madebetween the PK results of cohort 1 and 2. Pharmacokinetic parametersC_(max), T½ and total AUC were calculated for plasma concentrations ofketoconazole following the single dose on Day 8. Descriptive statistics(count, mean, median, standard deviation, minimum, maximum, and %coefficient of variation) were provided. Ketoconazole concentrationswere listed and summarized. GM means of C_(max) and total AUC werecompared for the single dose in this study to the combined data ofreported 400 mg single doses of ketoconazole of healthy subjects fromthe literature.

The mean (±SD) age of subjects was 29.4±6.8 years, and the mean BMI atscreening was 25.61±3.27 kg/m2. Seven of twelve subjects (58.3%) wereWhite, and 5/12 (41.7%) were Black/African American. Five of the 12subjects (41.7%) were of Hispanic or Latino ethnicity.

PHARMACOKINETIC (PK) RESULTS: PK data for mifepristone and metaboliteswas available for eleven of the 12 enrolled subjects and data forketoconazole PK analyses was available for 10 subjects. Concentrationsof mifepristone and each metabolite were above the limits of detectionduring the entire sampling duration from Day 7 predose to Day 13 (end ofstudy). mifepristone plasma concentrations showed a rapid initialdecline followed by a slow decline over time and metabolites peakedlater relative to parent mifepristone as expected. Mean RU 42633 and RU42848 exposure was similar or even greater than that for mifepristone,while RU 42698 exposure was lower. Ketoconazole PK after a single doseon Day 8 was readily computed. Co-administration of ketoconazoleincreased mifepristone and metabolite exposure. In the presence of 400mg ketoconazole on Day 8, Cohort 1 mifepristone C_(max) and AUC0-24increased by 20% and 25% relative to the prior Day 7 withoutketoconazole. This effect was slightly greater at 600 mg OD mifepristonein Cohort 2, where C_(max) and AUC₀₋₂₄ increased by 39% and 28% betweenDay 7 and Day 8. A dose of 600 mg OD mifepristone (Cohort 2) resulted inhigher mifepristone and metabolite exposure relative to a dose of 300 mgOD (Cohort 1) both alone and in the presence of 400 mg ketoconazole.This increase was less than proportionate to the two-fold doseincrement. On Day 7 without ketoconazole, mifepristone C_(max) andAUC₀₋₂₄ at 600 mg OD were 42% and 48% greater than at 300 mg OD. Thisdose effect was greater in the presence of 400 mg ketoconazole. Day 8mifepristone C_(max) and AUC₀₋₂₄ were 65% and 52% greater at 600 mg ODthan at 300 mg OD. mifepristone half-life on Day 8 in the presence of400 mg ketoconazole was similar between the two mifepristone doselevels. Day 8 half-life was 13% greater at 600 mg OD than at 300 mg OD.Ketoconazole exposure following a single 400 mg dose on Day 8 of aregimen of 600 mg OD mifepristone was 37% and 36% higher (C_(max) andAUCinf) relative to a mifepristone regimen of 300 mg OD. Ketoconazolehalf-life on either mifepristone regimen was not appreciably different.The addition of a single dose of 400 mg ketoconazole to 300 mg or 600 mgOD mifepristone on Day 8 resulted in exposure increases in C_(max) andAUC₀₋₂₄ that were similar to historical values at 600 mg or 1200 mg ODin the fasted state and 1200 mg OD in the fed state, respectively.Although the increase in exposure due to the addition of ketoconazolewas only between 20% and 39% in absolute terms, the resulting exposurewas similar to that of a dose 2 to 3 times greater. This is believed tobe due to a lack of dose-proportional kinetics for mifepristone.

The mean PK parameters and results from this study are presented inTable 2.

The abbreviations and symbols used in Table 2 have the followingmeanings:

“Tmax” indicates time to maximum observed plasma concentration; “Tmin”indicates time to minimum observed concentration within the 24 hourdosing interval; “C_(max)” indicates maximum observed plasmaconcentration; “C_(min)” indicates minimum observed concentration withinthe 24 hour dosing interval; “C_(avg)” indicates average steady-stateconcentration and is defined as drug input rate (Ro) divided by drugremoval rate (CLss) (C_(avg)=Ro/CLss, where f cancels out; this equationreduces to C_(avg)=AUCtau/tau); “AUC₀₋₂₄” indicates area under theplasma concentration versus time curve from time 0 to 24 hourspost-dose, calculated using the linear trapezoidal rule (this is thesame as AUCtau where tau is 24 hours or 1 day); “% Fluct” indicatespercent fluctuation in drug concentrations at steady-state computed as %Fluct=100×(C_(max)−C_(min))/C_(avg).

Drug-drug interaction (DDI) effects of ketoconazole on mifepristone andof mifepristone on ketoconazole were studied. A single 400 mg dose ofketoconazole caused a detectable increase in mifepristone exposure atmifepristone doses of 300 and 600 mg OD, and mifepristone at these dosescaused a detectable increase in ketoconazole exposure. Although theincrease in mifepristone exposure due to the addition of ketoconazolewas only between 20% and 39% in absolute terms, the resulting exposurewas similar to that of a dose 2 to 3 times greater. This is believed tobe due to a lack of dose-proportional kinetics for mifepristone.Predominantly mild AEs occurred and were observed primarily in subjectsadministered ketoconazole and mifepristone 600 mg.

Example 3

A Phase 1, single-center, open-label study was performed to study theeffect of oral twice-daily doses of 200 mg of ketoconazole given withmultiple oral once-daily doses of 600 mg of mifepristone in healthy malevolunteers, during which all drug administrations were given after atypical meal (34% fat content). An objective of this study was todetermine the effect of ketoconazole 200 mg twice daily on the PK ofmifepristone 600 mg once daily when both drugs were administered withfood. A single dose of ketoconazole was administered on Day −1. Duringmultidose administration, mifepristone was administered on Days 1-17 andketoconazole on Days 13-17; follow-up continued on Days 18-31. Sixteensubjects were enrolled (mean age 31.9 years; 8 black, 6 white, 2 other),and two subjects discontinued before starting themifepristone/ketoconazole combination treatment.

The study was a two period study design. In Period 1: 600 mgmifepristone was administered once daily from Day 1 to Day 12;pharmacokinetic samples were taken before each dose for assay ofmifepristone and active metabolites (mono-demethylated metabolite, RU42633; hydroxylated metabolite, RU 42698; and di-demethylatedmetabolite, RU 42848) to confirm that steady-state was achieved, and fora dose-interval concentration-profile on Day 12. In Period 2: 600 mgmifepristone once daily was continued in combination with 200 mgketoconazole twice daily from Days 13 to 17; pharmacokinetic sampleswere taken for assay of both mifepristone and metabolites, andketoconazole before dosing on Days 13 to 17, and on Day 17 for adose-interval concentration-time profile

A secondary objective was to determine if the effect of 200 mg BIDketoconazole on the PK of co-administered 600 mg OD mifepristone atsteady-state exceeded exposure to mifepristone and metabolites comparedto that of 1200 mg OD mifepristone with food, the labeled dosing regimenwith the highest mean observed exposure in healthy subjects.

Effects of Co-Administration with Ketoconazole on Mifepristone andMetabolites: The concentrations of mifepristone and the hydroxylatedmetabolite, RU 42698, were higher on Day 17 (600 mg mifepristone dailyco-administered with 200 mg ketoconazole twice daily) than on Day 12(mifepristone alone). Concentrations of RU 42633 and RU 42848 weresimilar on Day 17 and Day 12. Results of the formal statistical analysisare shown in Table 3.

For mifepristone, the geometric mean ratio of test to reference forC_(max) was 127.59% (90% CI:116.66, 139.54, where “CI” means “confidenceinterval” and “90% CI” means “90% confidence interval”) and for AUC₀₋₂₄was 138.01% (90% CI:127.12, 149.84). The lower bound of the 90%confidence intervals exceeded 100% and the upper bound exceeded 125%.Thus, co-administration with ketoconazole increased mifepristoneexposure. Similarly, for metabolite RU 42698, the lower bounds of the90% confidence intervals exceeded 100% and both geometric mean ratiosand the upper bound of the 90% confidence interval exceeded 125%, andthus exposure to this metabolite was increased by ketoconazole.

For metabolites RU 42848 and RU 42633, the calculated geometric meanratios and 90% confidence intervals of exposure ratios were within thestandard 80:125 comparison interval and thus not affected byketoconazole.

Effects of Co-administration with mifepristone on Ketoconazole: Theplasma concentration-time profiles of ketoconazole given twice dailywith mifepristone on Day 17 were much higher than for ketoconazole givenas a single dose alone on Day −1. Results of the formal statisticalanalysis are shown in Table 4.

The geometric mean ratio of test to reference for C_(max) was 252.71%(90% CI: 214.85, 297.26) and for AUC was 365.36% (90% CI:333.78,399.93). Thus, the geometric mean ratio and both lower and upper boundsof the 90% confidence intervals were entirely above the standard 80:125comparison interval and exposure on Day 17 (with mifepristone) washigher than on Day −1 (ketoconazole alone).

Comparison of Mifepristone Exposure with mifepristone Labeled Doses: Theconcentration-time plots showed that mean mifepristone concentrations onDay 17 in the present study were less than those in the fed condition ina previous “historic” study in which subjects received 1200 mgmifepristone daily for seven days. Mifepristone was administered to thesubjects within thirty minutes following a typical meal (34% fat) inboth the present study and in the historic study. Results of the formalstatistical analysis are shown in Table 5.

For mifepristone, the geometric mean ratio of test to reference forC_(max) was 84.64% (90% CI:72.92, 98.23); for AUC₀₋₂₄ it was 87.27% (90%CI:74.72, 101.94). The 90% confidence intervals were below andoverlapping the standard 80:125 comparison interval. The meanmifepristone concentrations in subject receiving 600 mg mifepristonefollowing a 34% fat meal were less than the mifepristone concentrationsin the historic study. As shown in Table 5, administration of 600 mgmifepristone in the fed state with ketoconazole resulted in mifepristoneconcentrations that were less than the mifepristone concentrationsmeasured in subjects receiving 1200 mg mifepristone daily in the absenceof ketoconazole. The Geometric Mean Ratio (GMR) values in Table 5suggest that mifepristone 600 mg co-administered with ketoconazoleyields mifepristone exposure 13-15% less than that of 1200 mgmifepristone in the absence of ketoconazole; for the metabolites,corresponding values range from an 18-19% decrease to a 17-18% increase.Thus, administration of 600 mg mifepristone daily with ketoconazoleresulted in mifepristone concentrations that were not higher than themean observed exposure at 1200 mg mifepristone; both treatments givenfollowing typical 34% fat meal. The value of 87% for GMR of the AUCssuggests that 900 mg mifepristone in the presence of ketoconazole wouldbetter match the exposure of a subject to 1200 mg mifepristone alonethan would 600 mg mifepristone in the presence of ketoconazole. Thus,these data also support the use of 900 mg mifepristone, and higher dosesas well, in the presence of ketoconazole.

For metabolite RU 42633, the 90% confidence intervals were within thestandard interval for C_(max) (geometric mean ratio 96.31%) and justoverlapping the lower bound of the standard interval for AUC₀₋₂₄(geometric mean ratio 91.34%). For metabolite RU 42698, confidenceintervals for both C_(max) and AUC₀₋₂₄ were overlapping and above thestandard interval (geometric mean ratio C_(max):116.55%;AUC₀₋₂₄:118.18%). For metabolite RU 42848, the 90% confidence intervalswere overlapping and below the standard interval for C_(max) (geometricmean ratio 82.45%) and AUC₀₋₂₄ (ratio 81.43%).

RU 42698 is a relatively minor metabolite and comprises 9% of the totalsteady-steady AUC₀₋₂₄ of mifepristone, RU42633, RU42698, RU42848 aloneand 13% of the total steady-steady AUC₀₋₂₄ in the presence ofketoconazole. Therefore, the increase in RU 42698 AUC₀₋₂₄ in thepresence of ketoconazole is considered to be minor.

FIG. 1 illustrates the results of measurements of plasma levels ofmifepristone, RU42633, RU42698, and RU 42848. These measurements weremade prior to the daily administration of mifepristone to the subject;thus the mifepristone and metabolite concentrations are “trough”concentrations. These results show that trough concentrations ofmifepristone and RU42848 were increasing day-by-day through the start ofketoconazole administration (Day 13). This indicates that steady stateconditions may not have been attained at the time of ketoconazoleadministration (which began on day 13).

FIG. 2 shows the plasma concentration profile of mifepristone before andafter inhibition of CYP3A by ketoconazole. Applicant notes that the time0 values (pre-dose) differ by ˜500 ng/ml, a difference that ismaintained relatively constant throughout much of the 24-hour samplinginterval. Thus, if the daily increase in trough concentrations betweendays 7 and 12 persevered through day 17, an unknown fraction of theincreased AUC (and C_(max)) between Day 12 and Day 17 could be due tofurther mifepristone administration rather than by an effect ofketoconazole alone. Thus, the values reported in Table 3 may overstatethe impact of CYP3A inhibition on exposure to mifepristone (andRU42848).

CONCLUSIONS: Co-administration of 600 mg mifepristone once daily with200 mg ketoconazole twice daily resulted in a mean increase in exposureto mifepristone of approximately 28% (C_(max):geometric mean ratio127.59% [90% CI:116.66, 139.54]) and 38% (AUC₀₋₂₄: geometric mean ratio138.01% [90% CI:127.12, 149.84]). These exposures are approximately 85%of those observed following the highest labeled dose of mifepristone(1200 mg daily).

The mean increase in exposure to the hydroxylated metabolite, RU 42698(approximately 70%), was somewhat greater than the increase in exposureto parent, resulting in exposure that was approximately 15 to 20% higherthan that following the highest labeled dose of mifepristone. Incontrast, co-administration with ketoconazole resulted in little changein exposure to the mono-demethylated metabolite, RU 42633, ordi-demethylated metabolite, RU 42848; exposure to these metabolites wassimilar to or slightly lower than exposure following the highest labeleddose.

The results presented in this example indicate that, with inhibition ofCYP3A (e.g., by co-administration of a strong CYP3A inhibitor such asketoconazole), a subject administered 900 mg mifepristone daily wouldexperience corresponding increases in mifepristone Cmax and AUC of27.59% and of 38.01%, respectively, which should yield systemicexposures similar in magnitude to those previously attained with 1200 mgdaily. Thus, the results of these measurements indicate that a subject,previously receiving a dose of 1200 mg mifepristone daily, may be safelyadministered a dose of 900 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen. Similarly, theresults of these measurements indicate that a subject, previouslyreceiving a dose of 900 mg mifepristone daily, may be safelyadministered a dose of 600 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen. In addition, theresults of these measurements indicate that a subject, previouslyreceiving a dose of 600 mg mifepristone daily, may be safelyadministered a dose of 300 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen.

No deaths or SAEs were reported during the study. Two subjectsdiscontinued due to AEs (moderate hypertension in one subject andmoderate bilateral rash on the upper arms and thighs in the othersubject, both during the mifepristone-only treatment period). At leastone TEAE was reported in 55.6% (9 of 16) of the subjects duringtreatment with mifepristone alone, in 57.1% (8 of 14) of the subjectsduring the mifepristone/ketoconazole treatment period, and in 7.1% (1 of14) of the subjects during the washout period.

The majority of TEAEs were mild. Four subjects reported moderate TEAEs:three subjects during treatment with mifepristone alone (1 eachreporting hypertension, rash, and vomiting) and 1 subject duringtreatment with mifepristone/ketoconazole (headache). All four moderateAEs were considered possibly or probably related to mifepristonetreatment. Only 1 of the moderate AEs was considered to be possiblyrelated to ketoconazole treatment. No severe TEAEs were reported.

Three subjects had elevated laboratory test results that were reportedas drug-related TEAEs. Mildly elevated liver enzymes were noted for onesubject starting on the morning of Day 14, and mildly elevatedcreatinine levels were noted for two subjects starting on the morning ofDay 14. Dosing was not interrupted for any of the subjects, and theevents resolved without sequelae.

No clinically significant effects of multiple-dose mifepristonetreatment with or without multiple-dose ketoconazole treatment wereobserved on hematology or urinalysis parameters, vital signs, or ECGs.

Example 4

This Example describes a Phase 1, single-center, open-label,fixed-sequence, drug-drug interaction study that studied the effect ofmultiple daily doses of oral itraconazole 200 mg, a strong inhibitor ofCYP enzymes, given with mifepristone 900 mg once per day (OD), inhealthy male subjects. This study was conducted in accordance with GoodClinical Practice under the guidance of an Institutional Review Boardand in accordance with applicable local legal and regulatoryrequirements. The schedule used during this study is shown in Table 6.

KORLYM® was supplied in 300 mg tablets for oral administration. Three orfour tablets were administered once daily (OD) to provide either the 900mg or 1200 mg per day dose.

Itraconazole was supplied

in 100 mg capsules for oral administration. Two capsules wereadministered once daily (OD) to provide the 200 mg per day dose.

All drug administrations were oral and were given after the morningmeal. Mifepristone, when given alone (1200 mg on days 1 to 14; 900 mg ondays 15 to 28), was administered within 30 minutes after breakfast;itraconazole (200 mg) was administered within 30 minutes afterbreakfast, and then mifepristone (900 mg) was administered approximately5 minutes after the administration of itraconazole (days 29 to 42).

The inclusion criteria required, among other criteria, that the subjectsbe healthy male subjects between the ages of 18 and 65, weigh more than110 pounds, and have a body mass index (BMI) of 18 to 32 kg/m². Thedesign included a Screening Period of up to 3 weeks (subjects werescreened at a time between days −21 to −1 prior to the first treatmentperiod), three 14-day treatment periods, and a Follow-Up (FU) Period of14 days for safety observation.

Subjects meeting the inclusion criteria (n=22) were administered drugdaily and blood samples were taken on the days indicated below duringPeriods 1-3 and on day 43 of the follow-up period. Subjects wereconfined to the clinical research unit on days −1 to 1 (prior to andincluding the day of administration of the first mifepristone dose); ondays 13-15; on days 27-29; and on days 42-43.

Treatment regimens and durations were as follows:

-   -   Period 1, Days 1-14: mifepristone 1200 mg once daily (OD) after        a meal.    -   (days 1, 2, 4, 6, 8, 11, 12, and 13); PK samples were taken 30        minutes prior to drug    -   (day 14) 24-hour PK sampling profiles were obtained.    -   Period 2, Days 15-28: mifepristone 900 mg OD after a meal.    -   (days 15, 16, 18, 20, 22, 25, 26, and 27); PK samples were taken        30 minutes prior to drug    -   (day 28) 24-hour PK sampling profiles were obtained    -   Period 3, Days 29-42: mifepristone 900 mg OD plus itraconazole        200 mg OD after a meal.    -   (days 29, 30, 32, 34, 36, 39, 40, and 41); PK samples were taken        30 minutes prior to drug    -   (day 42) 24-hour PK sampling profiles were obtained

Subjects presented at the Clinical Research Unit (CRU) after an 8-hourovernight fast, then predose PK samples were taken and other evaluations(predose electrocardiograms (ECGs), plasma cortisol and ACTH, serumchemistry tests) were performed. Subjects consumed a breakfast meal, andthe drug(s) (mifepristone monotherapy or in combination withitraconazole) was/were administered within about 30 minutes afterconsumption of breakfast. On the specific days indicated above,additional blood draws for determining 24-hour PK profiles wereperformed.

Safety and tolerability was assessed by adverse events (AEs) monitoring,measurement of vital signs, 12-lead ECG recordings, physicalexaminations, and by clinical laboratory safety tests.

Pharmacokinetic (PK) parameters measured and computed included AUC (areaunder the concentration−time curve), AUC₀₋₂₄ (AUC values from time 0 to24 hours postdose), C_(max) (maximum concentration), and Css (averagesteady-state concentration, calculated as AUC₀₋₂₄/24).

PK parameters were computed for mifepristone and its three majormetabolites (RU-42633, RU-42698, and RU-42848) using a non-compartmentalanalysis method in which AUC₀₋₂₄ was computed using the linear trapezoidrule.

FIG. 3 shows the plasma concentration profile of mifepristone measuredin healthy male volunteers over the course of twenty four hours sincedosing on day 14 (Visit 1; once-daily administration of 1200 mgmifepristone alone; triangles); on day 28 (Visit 2; once-dailyadministration of 900 mg mifepristone alone; circles); and on day 42(Visit 3; once-daily administration of 900 mg mifepristone and of 200 mgitraconazole; squares). The maximum exposure (mifepristone plasmaconcentration) was observed at about 4 hours after drug administrationfor mifepristone alone and also for mifepristone administered withitraconazole.

Administration of itraconazole along with mifepristone increasedexposure (plasma levels) of mifepristone as compared to mifepristonealone, so that, as expected, the maximum exposure for 900 mgmifepristone alone was less than the maximum exposure for 1200mifepristone alone. However, surprisingly, the maximum exposure measuredfor 900 mg mifepristone with 200 mg itraconazole was not very differentthan the maximum exposure for 1200 mifepristone alone. This is shown inTable 7, which presents plasma levels of mifepristone and three of itsmetabolites, RU-42633, RU-42698, and RU-42848, measured in subjectsadministered 900 mg mifepristone OD with 200 mg itraconazole OD andplasma levels measured in subjects administered 1200 mg mifepristone ODalone. The ratios (as percent) of C_(max) and AUC₀₋₂₄ for (900 mgmifepristone+200 mg itraconazole)/(1200 mg mifepristone) are presentedin the column labeled “Ratio (%)” (the ratio of the C_(max) and AUC₀₋₂₄geometric means determined within the limits of the 90% confidenceinterval).

The geometric mean ratio (%) for C_(max) (mifepristone C_(max) observedfor subjects receiving 900 mg mifepristone OD and 200 mg itraconazoleOD) divided by (mifepristone C_(max) observed for subjects receiving1200 mg mifepristone OD alone) was about 98%. The AUC geometric meanratio (%) of (mifepristone AUC₀₋₂₄ observed for subjects receiving 900mg mifepristone OD and 200 mg itraconazole OD) divided by (mifepristoneAUC₀₋₂₄ observed for subjects receiving 1200 mg mifepristone OD alone)was about 97%. These data demonstrate that the mifepristone maximumexposure for 900 mg mifepristone OD with 200 mg itraconazole OD was notgreater than, but was nearly equivalent to, the mifepristone maximumexposure for 1200 mg mifepristone OD.

Thus surprisingly, the maximum exposure for 900 mg mifepristone OD whenadministered with 200 mg itraconazole OD was about the same as themaximum exposure for 1200 mg mifepristone OD alone. This shows thatconcomitant administration of itraconazole did not cause extremely highlevels of mifepristone.

Table 8 presents plasma levels of mifepristone and three of itsmetabolites, RU-42633, RU-42698, and RU-42848, measured in subjectsadministered 900 mg mifepristone OD with 200 mg itraconazole OD andplasma levels measured in subjects administered 900 mg mifepristone ODalone. Table 8 also includes a column labeled “Ratio (%)” presenting thegeometric mean ratios determined within the limits of the 90% confidenceinterval for mifepristone and its metabolites, thus providing relativemeasures of the plasma levels of mifepristone and its metabolites(plasma levels obtained with 900 mg mifepristone OD with 200 mgitraconazole OD divided by plasma levels obtained with 900 mgmifepristone OD).

Table 8 presents this geometric mean ratio (%) data for mifepristone andthe three mifepristone metabolites RU-42633, RU-42698, and RU-42848comparing the geometric mean plasma levels measured in subjectsadministered 900 mg mifepristone OD with 200 mg itraconazole OD with thegeometric mean plasma levels measured in subjects administered 900 mgmifepristone OD alone. The ratio of mifepristone C_(max) was about 120%(C_(max) measured in subjects administered 900 mg mifepristone OD with200 mg itraconazole OD divided by C_(max) measured in subjectsadministered 900 mg mifepristone OD alone). The ratio of mifepristoneAUC₀₋₂₄ was about 110% (AUC₀₋₂₄ measured in subjects administered 900 mgmifepristone OD with 200 mg itraconazole OD divided by AUC₀₋₂₄ measuredin subjects administered 900 mg mifepristone OD alone).

As indicated in Tables 7 and Table 8 for mifepristone and for themifepristone metabolites RU-42633, RU-42698, and RU-42848, the plasmalevels obtained for 900 mg mifepristone OD and 200 mg itraconazole ODwere close to those obtained by 1200 mg mifepristone OD alone, and wereonly about 20% higher (or less) than those levels obtained by 900 mgmifepristone OD alone. Thus, administration of 900 mg of mifepristone ODwith 200 mg OD of a strong CYP3A inhibitor such as itraconazole providesabout the same plasma mifepristone levels as does administration of 1200mg mifepristone alone.

1200 mg OD mifepristone is a safe dose approved for use by the U.S. Foodand Drug Administration (FDA). The similarity in plasma levels formifepristone and its metabolites obtained with 900 mg mifepristone ODwith 200 mg itraconazole OD, as compared to those plasma levels obtainedwith 1200 mg mifepristone OD alone, indicates that 900 mg mifepristoneOD may be safely administered with itraconazole.

Since itraconazole is a strong CYP3A inhibitor, and since itraconazoleis considered an exemplar strong CYP3A inhibitor and may be used todetermine the effects of the class of strong CYP3A inhibitors (see FDA“Clinical Drug Interaction Studies—Study Design, Data Analysis, andClinical Implications Guidance for Industry”, pages 10-11(https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf), theseresults indicate that mifepristone may also be safely administered withother strong CYP3A inhibitors (such as, e.g., ketoconazole,itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,amprenavir and fosamprenavir, clarithromycin, conivaptan,lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, andvoriconazole). In addition, since less strong CYP3A inhibitors would beexpected to have smaller effects on plasma levels of mifepristone andits metabolites, these results indicate that mifepristone may also besafely administered with other CYP3A inhibitors in addition to thoselisted above, including CYP3A inhibitors that are not strong CYP3Ainhibitors (such as, e.g., fluconazole, cimetidine, boceprevir, andtelaprevir).

Example 5

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 1200 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 900 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 6

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 900 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 600 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 7

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 600 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 300 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 8

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 1500 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 1200 mg,so that the patient receives concomitant administration of ketoconazoleand mifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

All patents, patent applications, and publications identified herein arehereby incorporated by reference herein in their entireties.

TABLE 1 Mean Ratio Product No. MIFEPRISTONE Confidence ID/ SubjectsTreatments Mean PK Parameters (SD) Interval Batch Enter/ Age: Inter-C_(max) AUC_(tot) AUC_(t) C_(max) AUC_(total) No. Study Study CompleteMean acting ng/ T_(max) ng · h/ ng · h/ T_(1/2) ng/ ng · h/m (NME)Objective Design (M/F) Range Substrate Drug mL h mL mL h mL L Mifepris-Effect of Phase 1, 12/12 28 MIFE 400 3398 median 116939 38111 37.1 1.151.05 tone ketoconazole open-label, (12 M) 20-44 300 mg mg/d (6.77) 2.00 (26850) (8768) (9.77) 0.81- 0.72- 300 mg 400 mg OD (or parallel C1 Keto1.63 1.54 Tablet 200 mg BID) group, 400 mg (C2/ (C2/ on PK of 300 singleMIFE OD C1) C1) Keto mg single dose, MIFE 400 4143 median 130925 4062537.4 200 dose multiple 300 mg mg/d (1736) 1.00  (60942) (16524) (18.5)mg Mifepristone keto doses, C2 Keto Tablet given fasted in healthy 200mg subjects BID MIFE = mifepristone, Keto = ketoconazole, AUC_(tot) =AUC_(total,) AUC_(τ) = AUC₀₋₂₄ hours following single dose of MIFE C1 =Cohort 1, C2 = Cohort 2

TABLE 2 Mean Ratio # MIFEPRISTONE Confidence Product Subjects TreatmentsMean PK Parameters (SD) Interval ID/ Enter/ Age: Inter- C_(max)AUC_(tot) AUC_(t) AUC_(τ) Batch # Study Study Complete Mean acting ng/mT_(max) ng · h/ ng · h/ T_(1/2) C_(max) ng · h/ (NME) Objective Design(M/F) Range Substrate Drug L h mL mL h ng/ml mL Mifepristone Effect of400 Phase 1, 12/10 29.8 MIFE 2700 median NCª 37734 1.19 1.25 300 mg mgsingle open- (12 M) 20-43 300 mg/d  (534) 3.0 (11905) 0.93- 0.88- Tabletdose of label, C1 Day 7 1.53 1.76 Keto ketoconazole parallel MIFE 400 mg3240 median NCª 47357 84.9 C1 C1 200 mg on PK an 8 day group, 300 mg/dKeto  (760) 2.1 (17239) (46.6) Day Day Tablet regimen of crossover C1Day 8 single 8/ 8/ 300 mg OD within dose Day 7 Day 7 Mifepristone groupMIFE 3818 median NCª 54174 1.39 1.28 (or 600 mg OD with 600 mg/d  (703)4.0  (7305) 1.13- 1.09- Mifepristone) multiple C2 Day 7 1.70 1.49 givenwith MIFE MIFE 400 mg 5264 median NCª 69112 96.2 C2 C2 moderate fatdoses, 600 mg/d Keto  (795) 4.0  (9077) (45.4) Day Day (34%) and C2 Day8 single 8/ 8/ breakfast single dose Day 7 Day 7 keto 1.42 1.48 dose, in1.13- 1.13- healthy 1.78 1.94 subjects Day 7 Day 7 C2/C1 C2/C1 1.65 1.521.30- 1.14- 2.08 2.02 Day 8 Day 8 C2/C1 C2/C1 MIFE = mifepristone, Keto= ketoconazole C1 = Cohort 1, C2 = Cohort 2 AUC_(τ) = AUC₀₋₂₄ hoursfollowing Day 7 or Day 8 dose of MIFE ^(a) AUC_(tot) = AUC_(total), notcomputed (NC) for multiple dosing

TABLE 3 Effects of Co-Administration with Ketoconazole on Mifepristoneand Metabolites Test: Day 17 - 600 mg mifepristone OD + 200 mgKetoconazole BID Reference: Day 12 - 600 mg mifepristone OD Ratio% LowerUpper Analyte Parameter N Test/Reference 90% CI 90% CI MifepristoneC_(max) 13 127.59 116.66 139.54 AUC₀₋₂₄ 13 138.01 127.12 149.84 RU 42633C_(max) 13 105.73 95.92 116.54 AUC₀₋₂₄ 13 102.33 94.31 111.03 RU 42698C_(max) 13 169.13 156.36 182.94 AUC₀₋₂₄ 13 166.86 155.06 179.57 RU 42848C_(max) 13 95.48 90.82 100.38 AUC₀₋₂₄ 13 94.88 91.33 98.56

TABLE 4 Effects of Co-Administration with Mifepristone on KetoconazoleTest: Day 17 - 600 mg mifepristone OD + 200 mg Ketoconazole BIDReference: Day -1 - 200 mg Ketoconazole Single Dose Ratio % Lower UpperParameter N Test/Reference 90% CI 90% CI C_(max) 14 252.71 214.85 297.26AUC 14 365.36 333.78 399.93

TABLE 5 Cross-study Comparison of Exposure to Mifepristone andMetabolites Test: Present Study Day 17 - 600 mg mifepristone OD + 200 mgKetoconazole BID Reference: Historic Study Day 7 - 1200 mg mifepristoneOD alone Ratio % Lower Upper Analyte Parameter Test/Ref 90% CI 90% CIMifepristone C_(max) 84.64 72.92 98.23 AUC₀₋₂₄ 87.27 74.72 101.94 RU42633 C_(max) 96.31 80.83 114.75 AUC₀₋₂₄ 91.34 76.95 108.43 RU 42698C_(max) 116.55 97.47 139.38 AUC₀₋₂₄ 118.18 97.90 142.66 RU 42848 C_(max)82.45 70.31 96.70 AUC₀₋₂₄ 81.43 69.71 95.11 All doses given within 30minutes after typical (34%) fat meal

TABLE 6 MIFEPRISTONE with and without ITRACONAZOLE Study Drug Dosing andPF Sampling Schedule Period 3— Period 1— Period 2— MifepristoneMifepristone Mifepristone 900 mg QD 1200 mg 900 mg Plus ITZ Follow-Up toQD QD 200 mg QD End of Study Out- Con- Out- Con- Out- Con- Con-Outpatient/ patient fined patient fined patient fined fined TerminationDay 1ª-12 13-14^(b) 15ª-26 27-28^(c) 29-41 42 43 44-55/56 ± 1 StudyTreatment ITZ X X MIFE X X X X X X PK Sampling MIFE PK PK PK PK PK PK PKtrough trough trough trough trough trough trough D1, 2, D13 D15, 16, D27D29, 4, 6, 8, PK profile 18, 20, 22, PK profile 30, 32, 24-h ^(f) 11, 1224-h ^(d) 25, 26 24-h ^(e) 34, 36, D14 D28 39, 40, 41 ITZ PK PK PKtrough trough trough D29, 30, 32, 34, 36, 39, 40, 41 ITZ = itraconazole,MIFE = mifepristone. Note: dosing windows on Days 13 and 14, 27, and 28,and 41 and 42 are ±30 min; on other days, dosing windows are ±2 h.^(a)Outpatient status on Days 1 and 15 begin after PK sampling iscomplete. ^(b)For the 24-h PK profile on Day 14, subjects are admittedon the morning of Day 13 and are discharged the moming of Day 15.^(c)For 24-h PK profile on Day 28, subjects are admitted on the morningof Day 27 and will remain in confinement through the morning of Day 43.^(d) 24-h sample is taken predose on Day 15. ^(e) 24-h sample is takenpredose on Day 29. ^(f) 24-h sample is taken predose on Day 43.

TABLE 7 MIFEPRISTONE and its METABOLITES: EXPOSURE DATA 900 mgMifepristone + 200 mg Itraconazole compared to 1200 mg MifepristoneGeometric Mean Ratio (%) (ratio of analyte with/without Geometric MeansItraconazole coadministration) 900 mg Mife + 200 mg 1200 mg 90%Confidence Itraconazole Mifepristone Ratio (%) Interval (%) MifepristoneCmax 4,260 4,360 97.69 87.43-109.16 AUC(0-24) 65,400 67,700 96.6289.33-104.52 RU-42633 Cmax 1,970 2,160 90.95 84.56-97.83  AUC(0-24)41,900 45,800 91.58 85.48-98.12  RU-42698 Cmax 897 853 105.1696.49-114.61 AUC(0-24) 18,600 16,900 110.14 103.31-117.42  RU-42848 Cmax1,520 1,770 86 79.61-92.91  AUC(0-24) 32,800 36,500 89.82 84.26-95.74 

TABLE 8 MIFEPRISTONE and its METABOLITES: EXPOSURE DATA 900 mgMifepristone + 200 mg Itraconazole compared to 900 mg MifepristoneGeometric Mean Ratio (%) (ratio of analyte with/without Geometric MeansItraconazole coadministration) 900 mg Mife + 200 mg 900 mg 90%Confidence Itraconazole Mifepristone Ratio (%) Interval (%) MifepristoneCmax 4,260 3550 120.17 107.55-134.28 AUC(0-24) 65,400 59600 109.72101.43-118.68 RU-42633 Cmax 1,970 1970 99.89 92.87-107.45 AUC(0-24)41,900 40,300 104.00 97.07-111.43 RU-42698 Cmax 897 755 118.83109.03-129.51 AUC(0-24) 18,600 15,100 123.09 115.46-131.24 RU-42848 Cmax1,520 1,630 93.61 86.66-102.13 AUC(0-24) 32,800 33,900 96.6890.70-103.06

What is claimed is:
 1. A method of controlling hyperglycemia secondaryto hypercortisolism in a patient with endogenous Cushing's syndrome,said patient taking an original once-daily dose of 1200 milligrams (mg)per day of mifepristone, the method comprising the steps of: reducingsaid original once-daily dose to an adjusted once-daily dose of 900 mgper day of mifepristone, and administering the adjusted once-daily doseof 900 mg per day of mifepristone to the patient when the patient isreceiving concomitant administration of a strong CYP3A inhibitor,wherein said strong CYP3A inhibitor is selected from the groupconsisting of ketoconazole, itraconazole, nefazodone, ritonavir,nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan,lopinavir, posaconazole, saquinavir, telaprevir, cobicistat,troleandomycin, tipranivir, paritaprevir, and voriconazole.
 2. Themethod of claim 1, wherein said strong CYP3A inhibitor is selected fromthe group consisting of nefazodone, ritonavir, nelfinavir, boceprevir,clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir,cobicistat, troleandomycin, tipranavir, and paritaprevir.
 3. The methodof claim 1, wherein said strong CYP3A inhibitor is ketoconazole.
 4. Themethod of claim 1 wherein said strong CYP3A inhibitor is itraconazole.5. The method of claim 1, wherein said strong CYP3A inhibitor isclarithromycin.
 6. A method of controlling hyperglycemia secondary tohypercortisolism in a patient with endogenous Cushing's syndrome, saidpatient taking an original once-daily dose of 900 milligrams (mg) perday of mifepristone, the method comprising the steps of: reducing saidoriginal once-daily dose to an adjusted once-daily dose of 600 mg perday of mifepristone, and administering the adjusted once-daily dose of600 mg per day of mifepristone to the patient when the patient isreceiving concomitant administration of a strong CYP3A inhibitor,wherein said strong CYP3A inhibitor is selected from the groupconsisting of ketoconazole, itraconazole, nefazodone, ritonavir,nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan,lopinavir, posaconazole, saquinavir, telaprevir, cobicistat,troleandomycin, tipranivir, paritaprevir, and voriconazole.
 7. Themethod of claim 6, wherein said strong CYP3A inhibitor is selected fromthe group consisting of nefazodone, ritonavir, nelfinavir, boceprevir,clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir,cobicistat, troleandomycin, tipranavir, and paritaprevir.
 8. The methodof claim 6, wherein said strong CYP3A inhibitor is ketoconazole.
 9. Themethod of claim 6, wherein said strong CYP3A inhibitor is itraconazole.10. The method of claim 6, wherein said strong CYP3A inhibitor isclarithromycin.
 11. A method of controlling hyperglycemia secondary tohypercortisolism in a patient with endogenous Cushing's syndrome, saidpatient taking an original once-daily dose of 1200 milligrams (mg) perday of mifepristone, the method comprising the steps of: reducing saidoriginal once-daily dose to an adjusted once-daily dose of 600 mg perday of mifepristone, and administering the adjusted once-daily dose of600 mg per day of mifepristone to the patient when the patient isreceiving concomitant administration of a strong CYP3A inhibitor,wherein said strong CYP3A inhibitor is selected from the groupconsisting of ketoconazole, itraconazole, nefazodone, ritonavir,nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan,lopinavir, posaconazole, saquinavir, telaprevir, cobicistat,troleandomycin, tipranivir, paritaprevir, and voriconazole.
 12. Themethod of claim 11, wherein said strong CYP3A inhibitor is selected fromthe group consisting of nefazodone, ritonavir, nelfinavir, boceprevir,clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir,cobicistat, troleandomycin, tipranavir, and paritaprevir.
 13. The methodof claim 11, wherein said strong CYP3A inhibitor is ketoconazole. 14.The method of claim 11, wherein said strong CYP3A inhibitor isitraconazole.
 15. The method of claim 11, wherein said strong CYP3Ainhibitor is clarithromycin.
 16. The method of claim 11, furthercomprising, at least one week after the first once-daily administrationof said adjusted once-daily dose of 600 mg per day of mifepristone,upwardly titrating said adjusted once-daily dose of 600 mg per day ofmifepristone to an upwardly titrated once-daily dose of 900 mg per dayof mifepristone, and administering the upwardly titrated once-daily doseof 900 mg per day of mifepristone to the patient when the patient isreceiving concomitant administration of a strong CYP3A inhibitor. 17.The method of claim 1, wherein said mifepristone administrationcomprises oral administration of mifepristone.
 18. The method of claim6, wherein said mifepristone administration comprises oraladministration of mifepristone.
 19. The method of claim 11, wherein saidmifepristone administration oral administration of mifepristone.
 20. Themethod of claim 16, wherein said mifepristone administration oraladministration of mifepristone.